Kinase inhibitor salts and compositions thereof

ABSTRACT

The present invention relates to kinase inhibitor C 8 -C 16  aliphatic sulfate salts, compositions containing kinase inhibitor C 8 -C 16  aliphatic sulfate salts and uses thereof.

This application is a continuation of U.S. patent application Ser. No.16/701,941 filed Dec. 3, 2019 which is a continuation of InternationalPatent Application Number PCT/US2019/036947, filed on Jun. 13, 2019,which claims the benefits of U.S. Provisional Patent Application Ser.No. 62/685,411, filed Jun. 15, 2018, U.S. Provisional Patent ApplicationSer. No. 62/791,356 filed Jan. 11, 2019 and U.S. Provisional PatentApplication Ser. No. 62/811,368 filed Feb. 27, 2019; each of which isherein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to kinase inhibitor salts formed byreacting the kinase inhibitor with a C₈-C₁₆ aliphatic sulfate. Thekinase inhibitor salts may be orally administered to subjects incombination with at least one pharmaceutically acceptable excipient.

The present invention also relates to pharmaceutically acceptablecompositions and dosage forms comprising the kinase inhibitor C₈-C₁₆aliphatic sulfate salts, methods for preparing the compositions anddosage forms and methods of treating various conditions such as cancercomprising the oral administration of the compositions and dosage forms.

BACKGROUND

Kinase inhibitors (KIs) are compounds that inhibit kinase enzymes andthereby interfere with the activation of proteins. KIs are commonly usedto treat cancers but are also being used to treat inflammatory andautoimmune diseases such as rheumatoid arthritis and Crohn's disease.

KIs often exhibit pH dependent solubility and thus erraticbioavailability following oral administration.

KIs are also known to exhibit large absorption fluctuations whenadministered under fasting conditions compared to administration in thepresence of a high fat meal or when administered with other drugs suchas gastric acid reducing agents, i.e., antacids, H₂ antagonists andproton pump inhibitors. For example, some of the KIs are known toexhibit a significant increase in pharmacokinetics values such asC_(max) (maximum plasma concentration) and AUC (area under the plasmaconcentration curve) when the compound is orally administered in thepresence of a high fat meal compared to the administration under fastingconditions. Similarly, the co-administration of KIs with gastric acidreducing agents or agents that increase gastric pH is known to reduceabsorption of KIs. As a result of the large potential fluctuations,restrictions on the time and conditions of KI administration may berequired resulting in unwanted inconvenience to the patient, unwantedside effects if not administered correctly or loss of efficacy.

Accordingly, it is an object of the present invention to provide novelKI salts and compositions comprising the KI salts which will improve KIabsorption following oral administration, reduce the absorptionvariation when the KI is orally administered with or without food and orreduce the absorption variation when co-administered with other drugssuch as gastric acid reducing agents.

SUMMARY OF THE INVENTION

The present invention obtains the above objectives and others.

The present invention encompasses KI salts wherein the salt is formed byreacting the KI with a C₈-C₁₆ aliphatic sulfate. In one embodiment, theKI salt is formed by reacting the KI with an alkaline or alkaline earthmetal lauryl sulfate or an alkaline or alkaline earth metal tetradecylsulfate.

The present invention also encompasses compositions and dosage formscomprising the KI C₈-C₁₆ aliphatic sulfate salts and at least onepharmaceutically acceptable excipient, preferably for oraladministration to a subject.

The present invention further encompasses methods for reducing oreliminating food effects that result from the oral administration ofKIs. More specifically, the present invention encompasses the oraladministration of compositions and/or dosage forms of the presentinvention to a subject, wherein the subject may be either in a fed stateor a fasted state. Upon oral administration of the compositions ordosage forms of the present invention, a KI plasma profile is obtainedwherein at least one pharmacokinetic parameter differs by less thanabout 40% under fed and fasted conditions. In various embodiments, thepharmacokinetic parameter may vary by less than about 35%, 30%, 25%,20%, 15%, 10%, or 5% under fed and fasted conditions. Thepharmacokinetic parameter that is independent of food may be, but is notlimited to, C_(max), AUC, T_(max), or combinations thereof. In certainembodiments, one or more dosage forms comprising the KI C₈-C₁₆ aliphaticsulfate salts and at least one pharmaceutically acceptable excipient areorally administered to cancer patients with or without food wherein thedose of the KI C₈-C₁₆ aliphatic sulfate salts administered with orwithout food does not require an adjustment in dose or a change in timeof administration.

The present invention also further encompasses methods for reducing oreliminating drug interactions that result from the oral administrationof KIs and the co-administration of other drugs such as gastric acidreducing agents or drugs that raise gastric pH. More specifically, thepresent invention encompasses the oral administration of compositionsand/or dosage forms of the present invention to a subject, wherein thesubject may also be receiving drugs that reduce gastric acid secretionor that raise gastric acid pH. Upon oral administration of thecompositions or dosage forms of the present invention, a KI plasmaprofile is obtained wherein at least one pharmacokinetic parameterdiffers by less than about 40% when the compositions or dosage forms ofthe present invention are administered with or without a drug thatreduces gastric acid secretion or that raise gastric acid pH. In variousembodiments, the pharmacokinetic parameter may vary by less than about35%, 30%, 25%, 20%, 15%, 10%, or 5% when the compositions or dosageforms of the present invention are administered with or without a drugthat reduces gastric acid secretion or that raise gastric acid pH. Thepharmacokinetic parameter that is independent of co-administration witha drug that reduces gastric acid secretion or that raises gastric acidpH maybe C_(max), AUC, T_(max), or combinations thereof. In certainembodiments, one or more dosage forms comprising the KI C₈-C₁₆ aliphaticsulfate salts and at least one pharmaceutically acceptable excipient areorally administered to cancer patients that are being co-administeredgastric acid reducing agents wherein the dose of the KI C₈-C₁₆ aliphaticsulfate salts does not require an adjustment in dose or a change in timeof administration.

The present invention also encompasses methods for reducing the totaloral daily dose of the KI. More specifically, the present inventionencompasses the oral administration of compositions and/or dosage formsprepared in accordance with the present invention wherein the totaldaily amount of the KI administered is at least 10%, 15%, 20%, 25%, 30%,35%, 40%, 45% or 50% lower than the currently U.S. Food and DrugAdministration approved total daily amount of the KI free base or nonC₈-C₁₆ aliphatic sulfate salt.

In one embodiment of the present invention, the composition or dosageform for oral administration is a hard or soft capsule or a tablet,comprising a KI C₈-C₁₆ aliphatic sulfate salt and a pharmaceuticallyacceptable carrier, preferably in an intimate mixture. In certainaspects of this embodiment, the hard or soft capsule can begelatin-based or non gelatin-based capsule. In certain aspects of thisembodiment, the pharmaceutically acceptable carrier is a liquid atambient conditions, i.e., 25° C. and standard atmospheric pressure orthe pharmaceutically acceptable carrier is a solid at ambient conditionsbut has a melting point above 25° C. but less than 120° C., preferablyless than 100° C. and most preferably less than 80° C. If thepharmaceutically acceptable carrier is a liquid at ambient conditions,the KI C₈-C₁₆ aliphatic sulfate salt and liquid carrier are mixed andthe resulting mixture is filled or formed into the hard or soft capsule.The liquid mixture may further comprise one or more pharmaceuticallyacceptable excipients such as a stabilizer which are described ingreater detail below. If the carrier is a solid at ambient temperature,the carrier may be heated to melt the carrier and the melted carrier andKI C₈-C₁₆ aliphatic sulfate salt are mixed prior to filling or forminginto the hard or soft capsule or formed into a tablet. Alternatively,the carrier maybe dissolved or dispersed in a solvent and combined withthe KI C₈-C₁₆ aliphatic sulfate salt alone or combined with the KIC₈-C₁₆ aliphatic sulfate salt and at least one additional pharmaceuticalacceptable excipient to create an intimate admixture of the carrier andKI C₈-C₁₆ aliphatic sulfate salt. Once the intimate admixture of the KIC₈-C₁₆ aliphatic sulfate salt and carrier is created, it may be driedand filled or formed into a hard or soft capsule or the intimateadmixture can be combined with at least one or more pharmaceuticallyacceptable excipients and the resulting combination filled or formedinto a hard or soft capsule or formed into a tablet.

In another embodiment of the present invention, the compositions and/ordosage forms comprise the KI C₈-C₁₆ aliphatic sulfate salts and acarrier with an HLB value of 10 or greater wherein the carrier with anHLB value of 10 or greater is selected from the group consisting of awetting agent, an emulsifying agent, a solubilizing agent, a surfactantor combinations thereof. In preferred embodiments, the KI C₈-C₁₆aliphatic sulfate salt and carrier with an HLB value of 10 or greaterare intimately mixed. In further embodiments, the composition is aliquid composition that may be orally administered to a subject or theliquid composition may be filled into a hard or soft capsule for oraladministration to a subject. The liquid mixture may further comprise oneor more pharmaceutically acceptable excipients such as a stabilizerwhich are described in greater detail below. Alternatively, thecomposition may be a solid or semi-solid composition such as a powder orgranulate that may be orally administered to a subject or the solid orsemi-solid composition may be formed into a tablet or filled into acapsule for oral administration to a subject.

The present invention further encompasses methods for preparing, formingand manufacturing the compositions and dosage forms comprising the KIC₈-C₁₆ aliphatic sulfate salts and at least one pharmaceuticallyacceptable excipient, preferably for oral administration to a subject.

The present invention also further encompasses methods of treatingpatients comprising orally administering the compositions and dosageforms comprising therapeutic amounts of the KI C₈-C₁₆ aliphatic sulfatesalts and at least one pharmaceutically acceptable excipient.

The present invention also encompasses novel polymorphic forms of the KIC₈-C₁₆ aliphatic sulfate salts, methods for making the novel polymorphicforms, compositions and dosage forms comprising the novel polymorphicforms and methods of treating patients with the novel polymorphic forms.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph of the mean in vivo plasma data provided in Example 5.

FIG. 2 is a graph of the mean in vivo plasma data provided in Example10.

FIG. 3 is an XRPD pattern of the dasatinib monolauryl sulfate salt ofExample 12.

FIG. 4 is an XRPD pattern of the dasatinib dilauryl sulfate salt ofExample 13.

FIG. 5 is a graph of the mean in vivo plasma data provided in Example20.

FIG. 6 is a graph of the mean in vivo plasma data provided in Example21D.

FIG. 7 is a graph of the mean in vivo plasma data provided in Example24.

FIG. 8 is a graph of the mean in vivo plasma data provided in Example32.

FIG. 9 is a graph of the mean in vivo plasma data provided in Example35.

FIG. 10 is an XRPD pattern of the nilotinib dilauryl sulfate salt ofExample 38.

FIG. 11 is a graph of the mean in vivo plasma data provided in Example40.

FIG. 12 is a graph of the mean in vivo plasma data provided in Example42G.

FIG. 13 is an XRPD pattern of the nilotinib monolauryl sulfate salt ofExample 46, crystallization method A.

FIG. 14 is an XRPD pattern of the nilotinib monolauryl sulfate salt ofExample 46, crystallization method C.

FIG. 15 is an XRPD pattern of the nilotinib monolauryl sulfate salt ofExample 46, crystallization method D.

FIG. 16 is an XRPD pattern of the dasatinib monolauryl sulfate salt ofExample 47, crystallization method A.

FIG. 17 is an XRPD pattern of the dasatinib monolauryl sulfate salt ofExample 47, crystallization method B.

FIG. 18 is an XRPD pattern of the dasatinib monolauryl sulfate salt ofExample 48, crystallization method C.

FIG. 19 is an XRPD pattern of the dasatinib monolauryl sulfate salt ofExample 48, crystallization method D.

FIG. 20 is an XRPD pattern of the dasatinib monolauryl sulfate salt ofExample 48A, crystallization method E.

FIG. 21 is a graph of the mean in vivo plasma data provided in Example50.

FIG. 22A-22C are graphs of the mean in vivo plasma data provided inExample 51A.

FIG. 23 is a graph of the mean in vivo plasma data provided in Example52A.

FIG. 24 is a graph of the mean in vivo plasma data provided in Example53A.

FIG. 25 is a graph of the mean in vivo plasma data provided in Example61A.

FIG. 26 is a graph of the mean in vivo plasma data provided in Example61B.

FIG. 27 is a graph of the mean in vivo plasma data provided in Example61C.

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is further described, it is to beunderstood that this invention is not limited to the particularembodiments described. It is also to be understood that the terminologyused herein is for the purpose of describing particular embodimentsonly, and is not intended to be limiting.

It should be noted that as used herein, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

As used herein, the term “normal storage conditions” refers to storageat room temperature, approximately 25° C. and approximately 60% relativehumidity for at least three months, preferably at least six months, andmost preferably at least one year. The dosage form in accordance withthe present invention should be stored in pharmaceutically acceptablecontainers such as glass bottles, plastic bottles, metal foil pouch, orblister packaging with or without a desiccant.

As used herein, the term “accelerated storage conditions” refers tostorage at approximately 40° C. and approximately 75% relative humidityfor at least two weeks or longer, one month or longer, two months orlonger, three months or longer, four months or longer, five months orlonger, or six months or longer. The dosage form in accordance with thepresent invention should be stored in pharmaceutically acceptablecontainers such as glass bottles, plastic bottles, metal foil pouch, orblister packaging with or without a desiccant.

The term “HLB” refers to the “hydrophilic-lipophilic balance” of asurfactant or emulsifier and is a measure of the degree to which it ishydrophilic or lipophilic and is determined by calculating values forthe different regions of the molecule, as described by Griffin WC,“Calculation of HLB Values of Non-Ionic Surfactants,” Journal of theSociety of Cosmetic Chemists, 5:259 (1954). HLB values range from 0 to20, with an HLB value of 0 corresponding to a completely lipophilicmolecule, and a value of 20 corresponding to a completely hydrophilicmolecule. HLB values are generally known and reported in the literaturesuch as the manufacturer's technical brochures.

The term “C_(max)” denotes the maximum plasma concentration obtainedduring the dosing interval.

The term “T_(max)” denotes the time to maximum plasma concentration(C_(max)).

The term “AUC” means an area under the drug concentration-time curve(AUC) calculated using linear trapezoidal summation for a specifiedinterval of time, for example, AUC₀₋₁₂ refers to the area under the drugconcentration-time curve from the time immediately precedingadministration to 12 hours after administration, AUC₀₋₂₄ refers to thearea under the drug concentration-time curve from the time immediatelypreceding administration to 24 hours after administration, AUC_(0-∞)refers to the area under the drug concentration-time curve from the timeimmediately preceding administration to infinity and AUC_(0-t) refers tothe area under the drug concentration-time curve from the timeimmediately preceding administration to the designated time point such a2 hours, 8 hours, 18 hours etc after administration. In someembodiments, the designated time point is the last time point of bloodsampling.

The pharmacokinetic values described herein are generally determinedaccording to methods known and understood by those in the art and aregenerally described in publications such as the United States Food andDrug Administration's (U.S. FDA) Guidance for Industry: Bioavailabilityand Bioequivalence Studies for Orally Administered Drug Products—GeneralConsiderations (March 2003); U.S. FDA's Guidance for Industry:Statistical Approaches to Establishing Bioequivalence (January 2001);and U.S. FDA's Guidance for Industry: Food-Effect Bioavailability andFed Bioequivalence Studies (December 2002), which are incorporatedherein by reference.

As used herein, and unless otherwise defined, the term “subject” refersto a mammal such as a human, monkey, cow, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig, preferablyhumans and includes healthy mammals and mammals affected with a diseasethat may be treated with the KI. A subject that is affected with adisease that may be treated with the KI is sometimes referred to as“patient”.

As used herein, and unless otherwise defined, the phrase“therapeutically effective amount” when used in connection with apharmaceutical composition or dosage form comprising the KI salt meansan amount of KI or salt thereof effective for treating a disease ordisorder disclosed herein, such as cancer.

As used herein, and unless otherwise defined, the phrases “intimatelymixed,” “intimate mixture” and the like refer to a combination of the KIsalt of the present invention and at least one pharmaceuticallyacceptable excipient, preferably a carrier with an HLB value of about 10or greater, preferably about 11 or greater and most preferably about 12or greater such as a wetting agent, emulsifying agent, solubilizingagent, surfactant or combinations thereof wherein the KI salt and atleast one pharmaceutically acceptable excipient are in intimate contactor close association with each other. The intimate mixture may beprepared by any procedure that enables through blending of the KI saltof the invention and the at least one pharmaceutically acceptableexcipient, preferably a carrier with an HLB value of about 10 orgreater. An example of a suitable process for achieving the intimatemixture includes dissolving, suspending or dispersing the KI salt in asolution or suspension containing the at least one pharmaceuticallyacceptable excipient, preferably a carrier with an HLB value of about 10or greater and optionally at least one additional pharmaceuticallyacceptable excipient such as a pharmaceutically acceptable solvent. Thepharmaceutically solvent may or may not be removed. Another example of asuitable process for achieving the intimate mixture includes employing aliquid excipient wherein the liquid comprises at least onepharmaceutically acceptable excipient with an HLB value of about 10 orgreater or melting one or more solid excipients wherein the meltcomprises at least one pharmaceutically acceptable excipient with an HLBvalue of about 10 or greater, to create a melted or liquid excipientcomposition comprising at least one excipient with an HLB value of about10 or greater, and dissolving, suspending or dispersing the KI salt inthe melted or liquid excipient composition. The liquid excipientcomposition comprising at least one excipient with an HLB value of about10 or greater, may also comprise one or more pharmaceutically acceptableexcipients and described in greater detail below. Other processes thatmay be used to achieve the intimate mixture of the KI salt and at leastone pharmaceutically acceptable excipient preferably with an HLB valueof about 10 or greater, include co-blending, co-screening,co-compacting, co-compressing or a combination thereof. Once theintimate mixture of the KI salt and at least one pharmaceuticallyacceptable excipient, preferably with an HLB value of about 10 orgreater, is prepared, the intimately mixed composition may be combinedwith at least one additional pharmaceutical excipient or carrier. Theintimate mixture may preferably comprise the KI salt and one, two orthree excipients prior to being combined with any additional excipients.

As used herein, and unless otherwise defined, the term “gastric acidreducing agent” refers to excipients and/or drugs that increase gastricpH or neutralize stomach acid such as antacids or compounds that reducegastric acid secretion such as H₂ antagonists or proton pump inhibitors.Examples of common antacids include but are not limited to sodiumbicarbonate, sodium citrate, magnesium trisilicate, aluminumtrisilicate, calcium carbonate and over the counter products such asTUMS and ALKA-SELTZER. Examples of H₂ antagonists include but are notlimited to antihistamines, cimetidine, ranitidine, famotidine,nizatidine, roxatidine and lafutidine. Examples of proton pumpinhibitors include but are not limited to omeprazole, lansoprazole,pantoprazole, rabeprazole, esomeprazole and dexlansoprazole.

As used herein, and unless otherwise defined, the terms“co-administration, “co-administered,” and “co-administer” refers to asubject receiving one or more non-KI drug or therapeutic agent duringthe course of the KI therapy. The one or more non-KI drugs ortherapeutic agents may be administered concurrently or sequentially withthe KI composition or dosage form of the present invention. Theconcurrent administration as used herein means the non-KI drug ortherapeutic agent is administered within 2 hours before or afteradministration of the KI composition or dosage form of the presentinvention, preferably within 1 hour before or after administration ofthe KI composition or dosage form of the present invention and morepreferably within 30 minute before or after administration of the KIcomposition or dosage form of the present invention. The sequentialadministration as used herein means administration of the non-KI drug ortherapeutic agent at any time before or after the administration of theKI composition or dosage form of the present invention and may includeadministration of the non-KI drug such as 4, 6, 8, 12, or 14 hoursbefore or after the administration of the KI composition or dosage form.

As used herein, and unless otherwise defined, the term “KI” or “KIs”refers to any compound or compounds that are pharmaceutically active andthat inhibits a kinase enzyme, preferably a tyrosine kinase enzyme.Preferably, the KIs are small molecules that generally employ the “nib”suffix in the name and include the tyrosine kinase inhibitors (TKIs)which generally employ the suffix “tinib” in the name, angiogenesisinhibitors which generally employ the suffix “anib” in the name andrapidly accelerated fibrosarcoma kinase inhibitors which generallyemploy the suffix “rafinib” in the name. Also included are focaladhesion kinase (FAK) inhibitors.

Examples of KIs that may be employed in the present invention include,but are not limited to acalabrutinib (commercially available under thetradename CALQUENCE), afatinib (commercially available under thetradename GILOTRIF), alectinib (commercially available under thetradename ALECENSA), apatinib, axitinib (commercially available underthe tradename INLYTA), bafetinib, baricitinib, bosutinib (commerciallyavailable under the tradename BOSULIF), brigatinib (commerciallyavailable under the tradename ALUNBRIG), cabozantinib (commerciallyavailable under the tradename COMETRIQ), canertinib, cediranib,ceritinib (commercially available under the tradename ZYKADIA),cobimetinib (commercially available under the tradename COTELLIC),crenolanib, crizotinib (commercially available under the tradenameXALKORI), dabrafenib (commercially available under the tradenameTAFINLAR), dasatinib (commercially available under the tradenameSPRYCEL), defactinib (commercially available from Verastem Oncology)enasidenib (commercially available under the tradename IDHIFA),entrectinib, erlotinib (commercially available under the tradenameTARCEVA), filgotinib, foretinib, fostamatinib (commercially availableunder the tradename TAVALISSE), gefitinib (commercially available underthe tradename IRESSA), glesatinib, ibrutinib (commercially availableunder the tradename IMBRUVICA), icotinib, imatinib (commerciallyavailable under the tradename GLEEVEC), lapatinib (commerciallyavailable under the tradename TYKERB), lestaurtinib, lenvatinib(commercially available under the tradename LENVIMA), linifanib,lucitanib, momelotinib, motesanib, mubritinib, neratinib (commerciallyavailable under the tradename NERLYNX), nilotinib (commerciallyavailable under the tradename TASIGNA), nintedanib (commerciallyavailable under the tradename OFEV), oclacitinib (commercially availableunder the tradename APOQUEL), olmutinib, osimertinib (commerciallyavailable under the tradename TAGRISSO), pacritinib, pazopanib(commercially available under the tradename VOTRIENT), ponatinib(commercially available under the tradename ICLUSIG), quizartinib,radotinib, regorafenib (commercially available under the tradenameSTIVARGA), rociletinib, ruxolitinib (commercially available under thetradename JAKAFI), saracatinib, savolitinib, semaxanib, sitravtinib,sorafenib (commercially available under the tradename NEXAVAR),sunitinib (commercially available under the tradename SUTENT),taselisib, tesevatinib, tivozanib, toceranib, tofacitinib (commerciallyavailable under the tradename XELJANZ), trametinib (commerciallyavailable under the tradename MEKINIST), upadacitinib, vatalanib,vandetanib (commercially available under the tradename CAPRELSA) andvemurafenib (commercially available under the tradename ZELBORAF).

Some of the more preferred KIs that are useful in the present inventioninclude but are not limited to acalabrutinib, afatinib, alectinib,axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib,crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib,fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib,neratinib, nilotinib, nintedanib, oclacitinib, osimertinib, pazopanib,ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib,vandetanib, and vemurafenib.

Additional examples of KIs that are useful in the present invention areKIs that contain

(i) a phenyl carboxamide moiety with the following structure:

(ii) an amino pyrimidine moiety with the following structure:

(iii) an amino pyrimidine moiety with the following structure:

or

(iv) a combination of the moieties described in (i), (ii) or (iii)

wherein A is H, C, N, O, S, P, halogen (F, Cl, Br, I) and/or A may bepart of a larger moiety such as a straight, branched or cyclic moietyfor example an alkyl, aryl, alkoxy, etc. In certain embodiments, the Asubstituent on the nitrogen of the phenyl carboxamide moiety (i) ispreferably H or C₁-C₄ alkyl

Examples of KIs that contain the phenyl carboxamide moiety (i) includebut are not limited to afatinib, cabozantinib, dasatinib, lenvatinib,neratinib, nilotinib, nintedanib, osimertinib, ponatinib, regorafenib,and trametinib.

Examples of KIs that contain one of the amino pyrimidine moieties (ii)or (iii) include but are not limited to afatinib, brigatinib, ceritinib,dabrafenib, dasatinib, defactinib, erlotinib, fostamatinib, gefitinib,ibrutinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib,ruxolitinib, tofacitinib and vandetanib.

In certain preferred embodiments, the KIs used in the present inventionwill contain: (a) a phenyl carboxamide moiety (i) and an aminopyrimidine moiety (ii) or (b) a phenyl carboxamide moiety (i) and anamino pyrimidine moiety (iii) as described above. Examples of KIs thatcontain both the phenyl carboxamide moiety (i) and one of the aminopyrimidine moieties (ii) or (iii) include but are not limited toafatinib, dasatinib, imatinib, nilotinib and osimertinib.

The KI C₈-C₁₆ aliphatic sulfate salts of the present invention may beformed by reacting the KI molecule with a C₈-C₁₆ aliphatic sulfate. Inone embodiment, the KI C₈-C₁₆ aliphatic sulfate salt is formed byreacting the KI with an alkaline or alkaline earth metal lauryl sulfateor an alkaline or alkaline earth metal tetradecyl sulfate. Examples ofpreferred alkaline or alkaline earth metal lauryl sulfate or an alkalineor alkaline earth metal tetradecyl sulfate include but are not limitedto sodium or potassium lauryl sulfate and sodium or potassium tetradecylsulfate. The most preferred anionic compounds used to prepare the KIsalts of the present invention are sodium lauryl sulfate or potassiumlauryl sulfate.

The KI C₈-C₁₆ aliphatic sulfate salts of the present invention may beformed by dissolving a KI compound (either in a free base or salt formsuch as the KI HCl salt, KI citrate salt, KI phosphate salt, KI mesylatesalt, KI maleate salt, or KI tosylate salt) in a suitable solvent suchas water, an organic solvent such as C₁-C₆ branched or straight chainalcohols, ethers, esters or ketones or mixtures thereof, an organicsolvent such as a C₃-C₁₂ branched or straight chain alkane or mixturesthereof, or a mixture of water and an organic solvent, adding a C₈-C₁₆aliphatic sulfate to the KI solution and mixing the resulting reactionmass. Alternatively, the C₈-C₁₆ aliphatic sulfate may be dissolved in asuitable solvent, adding the KI compound (either in a free base or saltform) to the C₈-C₁₆ aliphatic sulfate solution and mixing the resultingreaction mass. The KI C₈-C₁₆ aliphatic sulfate salt of the presentinvention may also be formed by dissolving the KI compound (either in afree base or salt form) in a suitable solvent, dissolving the C₈-C₁₆aliphatic sulfate in a suitable solvent, combing the KI compoundsolution and the C₈-C₁₆ aliphatic sulfate solution and mixing theresulting reaction mass. The solvent is removed from the resultingreaction mass by conventional techniques such as evaporation orfiltration to isolate the KI C₈-C₁₆ aliphatic sulfate salt. The isolatedKI C₈-C₁₆ aliphatic sulfate salt of the present invention may be used inthe compositions and dosage forms described herein.

In some embodiments of the present invention the dissolved KI compoundmay be reacted with an acid, preferably a strong acid and mostpreferably an inorganic acid to protonate one or more of the nitrogenatoms. Once the KI is protonated it is combined with the C₈-C₁₆aliphatic sulfate for form the KI C₈-C₁₆ aliphatic sulfate salt.

The molar ratio of C₈-C₁₆ aliphatic sulfate to KI compound in thereaction mass could range from about 0.5 moles of C₈-C₁₆ aliphaticsulfate to about 6 moles of C₈-C₁₆ aliphatic sulfate for each mole of KIbase present in the reaction mass, preferably about 0.75 moles of C₈-C₁₆aliphatic sulfate to about 5 moles of C₈-C₁₆ aliphatic sulfate for eachmole of KI base present in the reaction mass and most preferably about0.85 moles of C₈-C₁₆ aliphatic sulfate to about 4 moles of C₈-C₁₆aliphatic sulfate for each mole of KI base present in the reaction mass.The KI C₈-C₁₆ aliphatic sulfate salt may also be formed during or aspart of the manufacturing of the compositions or dosage forms of thepresent invention. In some embodiments of KI mono C₈-C₁₆ aliphaticsulfate salt, the molar ratio of C₈-C₁₆ aliphatic sulfate to KI compoundin the reaction mass could range from about 0.8 moles of C₈-C₁₆aliphatic sulfate to about 1.3 moles of C₈-C₁₆ aliphatic sulfate foreach mole of KI base present in the reaction mass. In some embodimentsof KI di C₈-C₁₆ aliphatic sulfate salt, the molar ratio of C₈-C₁₆aliphatic sulfate to KI compound in the reaction mass could range fromabout 1.6 moles of C₈-C₁₆ aliphatic sulfate to about 2.5 moles of C₈-C₁₆aliphatic sulfate for each mole of KI base present in the reaction mass.The KI C₈-C₁₆ aliphatic sulfate salts of the present invention may be aKI mono C₈-C₁₆ aliphatic sulfate salt or a KI multi C₈-C₁₆ aliphaticsulfate salt such as KI di C₈-C₁₆ aliphatic sulfate salt, a KI triC₈-C₁₆ aliphatic sulfate salt, a KI tetra C₈-C₁₆ aliphatic sulfate saltor a KI penta C₈-C₁₆ aliphatic sulfate salt. Unless otherwise indicated,the term KI C₈-C₁₆ aliphatic sulfate salts as used herein encompassesthe mono and multiple aliphatic sulfate salts and similarly the term KIlauryl sulfate salts encompasses the mono and multiple lauryl sulfatesalts.

The present invention also encompasses compositions and dosage formscomprising the KI C₈-C₁₆ aliphatic sulfate salts and at least onepharmaceutically acceptable excipient, preferably for oraladministration to a subject. The compositions and dosage forms may be asolid, semi-solid or liquid, wherein the KI C₈-C₁₆ aliphatic sulfatesalt is combined with pharmaceutically acceptable excipients such asfillers, diluents, binders, stabilizing agents, lubricants,disintegrants, wetting/solubilizing/emulsifying agents or mixturesthereof. The pharmaceutically acceptable excipients are well known inthe art and are described in Remington, The Science and Practice ofPharmacy, 21^(st) ed. (2006), pp. 1058-1092, and Handbook ofPharmaceutical Excipients, 6^(th) ed. (2009). Representative examples ofthe various pharmaceutically acceptable excipients employed in theembodiments of the present invention are provided below.

The solid and semi-solid compositions and dosage forms include powders,granules, pellets, mini-tablets, tablets, or capsules and may be made bymethods known in the art such as direct compression, wet or drygranulation, and extrusion spheronization.

The liquid compositions and dosage forms include solutions, suspensions,or dispersions and these may also be made by methods known in the art.

In one embodiment of the present invention, the composition or dosageform for oral administration is a tablet or a hard or soft gelatincapsule comprising a KI C₈-C₁₆ aliphatic sulfate salt and apharmaceutically acceptable carrier, preferably in an intimate mixture.In certain aspects of this embodiment, the pharmaceutically acceptablecarrier is a liquid at ambient conditions, i.e., 25° C. and standardatmospheric pressure, or the pharmaceutically acceptable carrier is asolid at ambient conditions but has a melting point above 25° C. butless than 120° C., preferably less than 100° C., more preferably lessthan 80° C. and most preferably less than 60° C. If the pharmaceuticallyacceptable carrier is a liquid at ambient conditions, the KI C₈-C₁₆aliphatic sulfate salt and liquid carrier are mixed and the resultingmixture is filled or formed into the hard or soft gelatin capsule. Theliquid mixture may also comprise one or more additional pharmaceuticallyacceptable excipients such as a stabilizer described in greater detailbelow.

If the carrier is a solid or semi-solid at ambient temperature, thecarrier may be mixed or granulated with the KI C₈-C₁₆ aliphatic sulfatesalt and optionally one or more additional pharmaceutically acceptableexcipients prior to forming into a tablet or filling or forming into ahard or soft gelatin capsule. Alternatively, if the carrier is a solidor semi-solid at ambient temperature the carrier may be heated to meltthe carrier and the melted carrier, KI C₈-C₁₆ aliphatic sulfate salt andoptionally one or more additional pharmaceutically acceptable excipientsare mixed prior to forming into a tablet or filling or forming into ahard or soft gelatin capsule.

In certain embodiments, the KI C₈-C₁₆ aliphatic sulfate salt isdissolved in the liquid carrier or dissolved in the melted carrier.Alternatively, the KI C₈-C₁₆ aliphatic sulfate salt is dispersed orsuspended in the liquid carrier or dispersed or suspended in the meltedcarrier.

Examples of liquid carriers that may be used in preparing the oraldosage forms of the present invention include but are not limited tofatty acids, medium chain triglycerides, fatty acid esters, fatty acidalcohols, vegetable oils such as corn oil, soy bean oil, olive oil, sunflower oil, peanut oil or mixtures thereof. In certain embodiments theliquid carrier should comprise about 10%, 15%, 20%, 25%, 30%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% 95% (w/w) of the compositionor any range encompassed by the foregoing values, preferably about 15%(w/w) to about 90% (w/w) and most preferably about 20% (w/w) to about85% (w/w) of the composition filled into the capsule.

Examples of solid carriers with a melting point between 25° C. and lessthan 120° C. include aliphatic alcohols, polyethylene glycol, such aspolyethylene glycol 1000 with a melting point of 37-40° C., polyethyleneglycol 1500 with a melting point of 44-48° C., hard fat (akahydrogenated vegetable glycerides), hydrogenate vegetable oil, vitamin Epolyethylene glycol succinate (aka TPGS), poloxamers (nonionicpolyoxyethylene-polyoxypropylene copolymers such as poloxamer 188,poloxamer 237, poloxamer 338 and poloxamer 407), polyoxylglycerides,polyoxyethylene stearates and waxes, such as carnauba wax, cetyl esterwax, microcrystalline wax, white wax, and yellow wax and combinations ofthe foregoing solid carriers. In certain embodiments, the solid carriershould comprise about 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%,22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, 50%,52.5%, 55%, 57.5%, 60%, 62.5%, 65%, 67.5%, 70%, 72.5%, 75%, 77.5%, 80%,82.5%, 85%, 87.5%, 90%, 92.5%, 95% (w/w) or any range encompassed by theforegoing values, preferably about 5% (w/w) to about 90% (w/w) and mostpreferably about 7.5% (w/w) to about 85% (w/w) of the composition filledinto the capsule or formed into a tablet.

Additional examples of the solid, semi-sold and liquid carriers that maybe used in preparing the solid, semi-solid or liquid dosage forms of thepresent invention including but not limited to hard gelatin capsules,soft gelatin capsules and tablets of the present invention includewetting agents, emulsifying agents, solubilizing agents, surfactants orcombinations thereof that exhibit an HLB value of about 10 or greater,preferably an HLB value of about 11 or greater, more preferably an HLBvalue of about 12 or greater and most preferably an HLB value of about14 or greater are described in detail below.

In another embodiment of the present invention, the compositions ordosage forms may comprise the KI C₈-C₁₆ aliphatic sulfate salt and oneor more wetting agent, emulsifying agent, solubilizing agent, surfactantor combinations thereof that exhibits an HLB value of about 10 orgreater, preferably an HLB value of about 11 or greater, more preferablyabout 12 or greater and most preferably about 14 or greater and at leastone additional pharmaceutically acceptable excipient. The KI C₈-C₁₆aliphatic sulfate salt may be present in the composition in an amount ofabout 1 wt % to about 80 wt % based on the total weight of thecomposition or dosage form, preferably about 2 wt % to about 70 wt %,more preferably about 2.5 wt % to about 60 wt % and most preferablyabout 3 wt % to about 50 wt %. In certain embodiments, the KI C₈-C₁₆aliphatic sulfate salt may be present in the composition in an amount ofabout 2 wt %, 3 wt %, 4 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, 10wt %, 11 wt %, 12 wt %, 13 wt %, 14 wt %, 15 wt %, 16 wt %, 17 wt %, 18wt %, 19 wt %, 20 wt %, 21 wt %, 22 wt %, 23 wt %, 24 wt %, 25 wt %, 26wt %, 27 wt %, 28 wt %, 29 wt %, 30 wt %, 31 wt %, 32 wt %, 33 wt %, 34wt %, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39 wt %, 40 wt %, 41 wt %, 42wt %, 43 wt %, 44 wt %, 45 wt %, 46 wt %, 47 wt %, 48 wt % 49 wt % 50 wt% or any range encompassed by the foregoing values. The one or morewetting agent, emulsifying agent, solubilizing agent, surfactant orcombinations thereof that exhibits an HLB value of about 10 or greater,preferably about 11 or greater, more preferably 12 or greater and mostpreferably about 14 or greater should be present in the composition ordosage form in an amount of 1 wt % or greater based on the total weightof the composition or dosage form, preferably in an amount of about 2 wt% or greater and most preferably in an amount of about 5 wt % or greaterbased on the total weight of the composition or dosage form. In certainembodiments, the one or more wetting agent, emulsifying agent,solubilizing agent, surfactant or combinations thereof that exhibits anHLB value of about 10 or greater, preferably about 11 or greater, morepreferably about 12 or greater and most preferably about 14 or greatershould be present in the composition or dosage form in an amount ofabout 1 wt % to about 90 wt %, preferably about 2 wt % to about 80 wt %and most preferably about 3 wt % to about 70 wt %. In certainembodiments, the one or more wetting agent, emulsifying agent,solubilizing agent, surfactant or combinations thereof that exhibits anHLB value of about 10 or greater may be present in the composition in anamount of about 2 wt %, 3 wt %, 4 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %,9 wt %, 10 wt %, 11 wt %, 12 wt %, 13 wt %, 14 wt %, 15 wt %, 16 wt %,17 wt %, 18 wt %, 19 wt %, 20 wt %, 21 wt %, 22 wt %, 23 wt %, 24 wt %,25 wt %, 26 wt %, 27 wt %, 28 wt %, 29 wt %, 30 wt %, 31 wt %, 32 wt %,33 wt %, 34 wt %, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39 wt %, 40 wt %,41 wt %, 42 wt %, 43 wt %, 44 wt %, 45 wt %, 46 wt %, 47 wt %, 48 wt %49 wt % 50 wt %, 51 wt %, 52 wt %, 53 wt %, 54 wt %, 55 wt %, 56 wt %,57 wt %, 58 wt %, 59 wt %, 60 wt % or any range encompassed by theforegoing values.

The one or more wetting agent, emulsifying agent, solubilizing agent,surfactant or combinations thereof that exhibits with an HLB value ofabout 10 or greater may be a non-ionic surfactant, an ionic surfactantor a combination thereof and is preferably a non-ionic surfactant.Examples of non-ionic surfactants that may be used includepolyethoxylated castor oil, a polyoxyethylene alkyl ester, apolyglycolyzed glyceride, a sorbitan fatty acid ester, a glycerin fattyacid ester, a fatty acid polyglyceride, a fatty acid alcohol polyglycolether, acetylene glycol, acetylene alcohol, an oxyalkylene blockpolymer, a polyoxyethylene alkyl ether, a polyoxyethylene alkylarylether, a polyoxyethylene styrylaryl ether, a polyoxyethylene glycolalkyl ether, a polyoxyethylene fatty acid ester, a polyoxyethylenesorbitan fatty acid ester, a polyoxyethylene glycerin fatty acid ester,a polyoxyethylene hydrogenated castor oil, a polyoxypropylene fatty acidester, polyoxylglycerides, polyoxyethylene stearates or a mixture of theforegoing. A further listing of possible non-ionic surfactants can befound on pages 1243-1249 of Martindale, The Extra Pharmacopoeia, 29^(th)ed. which is incorporated herein by reference.

The one or more wetting agent, emulsifying agent, solubilizing agent,surfactant or combinations thereof that exhibits an HLB value of about10 or greater may be a non-ionic surfactant such as fatty alcohol acidor amide ethoxylates, monoglyceride ethoxylates, sorbitan esterethoxylates alkyl polyglycosides, and mixtures thereof. Examples ofthese non-ionic surfactants include but are not limited topolyoxyethylene derivatives of polyol esters, such as Polysorbate 20(commercially available under the tradename TWEEN® 20), Polysorbate 40(commercially available under the tradename TWEEN® 40) Polysorbate 60(commercially available under the tradename TWEEN® 60), and Polysorbate80 (commercially available under the tradename TWEEN® 80).

The one or more wetting agent, emulsifying agent, solubilizing agent,surfactant or combinations thereof that exhibits an HLB value of about10 or greater may be a polyoxyethylene castor oil such as polyoxylcastor oil or polyoxyl hydrogenated castor oil or mixtures thereof.Examples of these surfactants include but are not limited to polyoxyl 35castor oil (commercially available under the tradename CREMAPHOR EL orKOLLIPHOR EL), polyoxyl 40 hydrogenated castor oil (commerciallyavailable under the tradename CREMOPHOR RH 40) and polyoxyl 60hydrogenated castor oil.

The one or more wetting agent, emulsifying agent, solubilizing agent,surfactant or combinations thereof that exhibits an HLB value of about10 or greater may be a polyoxyethylene alkyl ether such as a polyoxylcetostearyl ether, polyoxyl cetyl ether, polyoxyl lauryl ether, polyoxyloleyl ether, polyoxyl stearyl ether or mixtures thereof.

The one or more wetting agent, emulsifying agent, solubilizing agent,surfactant or combinations thereof that exhibits an HLB value of about10 or greater may be a tyloxapol, a poloxamer, i.e., a nonionicpolyoxyethylene-polyoxypropylene copolymers such as poloxamer 188,poloxamer 237, poloxamer 338, poloxamer 407 or a combination thereof.

The one or more wetting agent, emulsifying agent, solubilizing agent,surfactant or combinations thereof that exhibits an HLB value of about10 or greater may be a fatty acid ester or fatty acid alcohol of apolyglyceride such as a caprylic/capric triglyceride (commerciallyavailable under the tradename MYIGLYOL).

In certain embodiments of the present invention, the compositioncomprises the KI C₈-C₁₆ aliphatic sulfate and one or more wetting agent,emulsifying agent, solubilizing agent, surfactant or combinationsthereof that exhibits an HLB value of about 10 or greater, preferably inan intimate mixture, and may also further comprise at least oneadditional secondary carrier with a low or no HLB value. The secondarycarrier may be one or more wetting agent, emulsifying agent,solubilizing agent, surfactant or combinations thereof that exhibits anHLB value of about less than 10, more preferably an HLB value of about 9or less, about 8 or less, and most preferably an HLB value of about 7 orless. Examples of the at least one additional secondary carriers with alow HLB value include non-ionic surfactants which include but are notlimited to polyethoxylated castor oil, a polyoxyethylene alkyl ester, apolyglycolyzed glyceride, a sorbitan fatty acid ester, a glycerin fattyacid ester, a fatty acid polyglyceride, a fatty acid alcohol polyglycolether, acetylene glycol, acetylene alcohol, an oxyalkylene blockpolymer, a polyoxyethylene alkyl ether, a polyoxyethylene alkylarylether, a polyoxyethylene styrylaryl ether, a polyoxyethylene glycolalkyl ether, a polyoxyethylene fatty acid ester, a polyoxyethylenesorbitan fatty acid ester, a polyoxyethylene glycerin fatty acid ester,a polyoxyethylene hydrogenated castor oil, a polyoxypropylene fatty acidester, or a mixture of the foregoing. A further listing of possiblenon-ionic surfactants with low HLB values can be found on pages1243-1249 of Martindale, The Extra Pharmacopoeia, 29^(th) ed. which isincorporated herein by reference.

In certain embodiments, the secondary carrier with an HLB value of aboutless than 10 is a medium chain (i.e., about 4 to about 20 carbon atoms,preferably about 6 to about 18 carbon atoms and most preferably about 6to and 14 carbon atoms) monoglyceride or diglyceride such as a glycerylcaprylate/caprate (commercially available under the tradename CAPMULMCM), a glyceryl caprylate (commercially available under the tradenameCAPMUL MCM C8), glyceryl caprate (commercially available under thetradename CAPMUL MCM C10), glyceryl monocaprylocaprate (commerciallyavailable under the tradename CAPMUL 471) or mixtures thereof.

In certain embodiments, the secondary carrier with an HLB value of aboutless than 10 is a polyoxylglyceride such as caprylocaproylpolyoxylglycerides, lauroyl polyoxylglycerides, linoleoylpolyoxylglycerides, oleoyl polyoxylglycerides, stearoylpolyoxylglycerides, and mixtures of the foregoing.

In certain embodiments, the secondary carrier with an HLB value of aboutless than 10 is a sorbitan ester or sorbitan fatty acid ester such assorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate,tyloxapol, and mixtures of the foregoing.

In certain embodiments, the secondary carrier with an HLB value of aboutless than 10 is a phospholipid or lecithin.

In certain embodiments, the secondary carrier is an oil, a medium chaintriglyceride, hydrogenated vegetable oil, suppository bases orcombinations thereof.

In certain embodiments, the secondary carrier with an HLB of about lessthan 10 is liquid at ambient temperature or exhibits a melting point ofabout 75° C. or less, about 70° C. or less, about 65° C. or less, about60° C. or less, about 55° C. or less, about 50° C. or less, about 45° C.or less or about 40° C. or less.

In the embodiments employing the secondary carrier with an HLB value ofabout less than 10, the amount of the secondary carrier with an HLBvalue about less than 10 may be about 1 wt % to about 90 wt % based onthe total weight of the composition, preferably about 5 wt % to about 85wt % and most preferably about 10 wt % to about 80 wt %. The forgoingweight percentages may be based on a single secondary carrier or acombination of secondary carriers. In certain embodiments, the one ormore wetting agent, emulsifying agent, solubilizing agent, surfactant orcombinations thereof that exhibits an HLB value of about less than 10may be present in the composition in an amount of about 5 wt %, 6 wt %,7 wt %, 8 wt %, 9 wt %, 10 wt %, 11 wt %, 12 wt %, 13 wt %, 14 wt %, 15wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, 20 wt %, 21 wt %, 22 wt %, 23wt %, 24 wt %, 25 wt %, 26 wt %, 27 wt %, 28 wt %, 29 wt %, 30 wt %, 31wt %, 32 wt %, 33 wt %, 34 wt %, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39wt %, 40 wt %, 41 wt %, 42 wt %, 43 wt %, 44 wt %, 45 wt %, 46 wt %, 47wt %, 48 wt % 49 wt % 50 wt %, 51 wt %, 52 wt %, 53 wt %, 54 wt %, 55 wt%, 56 wt %, 57 wt %, 58 wt %, 59 wt %, 60 wt %, 61 wt %, 62 wt %, 63 wt%, 64 wt %, 65 wt %, 66 wt %, 67 wt %, 68 wt %, 69 wt %, 70 wt %, 71 wt%, 72 wt %, 73 wt %, 74 wt %, 75 wt %, 76 wt %, 77 wt %, 78 wt %, 79 wt% 80 wt % or any range encompassed by the foregoing values.

The compositions and dosage forms of the present invention may alsooptionally comprise additional pharmaceutically acceptable excipientssuch as stabilizers, fillers, viscosity enhancing agents, binders,disintegrants, lubricants, glidants, flavoring agents, and combinationsthereof.

In certain embodiments the dosage form of the present invention is asolid or semi-solid oral dosage form, preferably a capsule or tabletthat comprises:

-   -   (i) about 1 wt % to about 60 wt % based on the total weight of        the solid composition or dosage form, preferably about 2 wt % to        about 55 wt % and most preferably about 5 wt % to about 50 wt %        of a KI C₈-C₁₆ aliphatic sulfate salt;    -   (ii) about 1 wt % to about 60 wt %, preferably about 2 wt % to        about 50 wt % and most preferably about 3 wt % to about 40 wt %        of one or more wetting agents, solubilizing agents, emulsifying        agents, surfactants or combinations thereof that exhibits an HLB        value of about 10 or greater, preferably an HLB value of about        11 or greater, more preferably an HLB value of about 12 or        greater and most preferably an HLB value of about 14 or greater;        and    -   (iii) at least one additional pharmaceutically acceptable        excipient selected from the group consisting of stabilizers,        fillers, viscosity enhancing agents, binders, disintegrants,        lubricants, glidants, flavoring agents, and combinations        thereof.

In further embodiments, such as a semi-solid embodiment, the oral dosageform may further comprise (iv) a viscosity enhancing agent that is asolid at ambient temperatures but that exhibits a melting point below120° C., preferably below 100° C., more preferably below 80° C. and mostpreferably below 60° C. If the dosage form comprises item (iv) aviscosity enhancing agent that is a solid at ambient temperatures butthat exhibits a melting point below 120° C., item (iv) should compriseabout 0.5 wt % to about 60 wt %, preferably about 1 wt % to about 55 wt% and most preferably about 5 wt % to about 50 wt % of the total weightof the composition.

Examples of stabilizers that may be used in the present inventioninclude, but are not limited to, antioxidants, drying agents, buffers,pH adjusting agents, or combination thereof. The stabilizer(s) ifpresent in the dosage form should be less than about 20% of the totalweight of the composition, preferably less than about 15% of the totalweight of the composition, and most preferably less than about 10% ofthe total weight of the composition. In certain embodiments, thestabilizer may be present in the composition in an amount of about 0.01wt %, 0.02 wt %, 0.03 wt %, 0.04 wt %, 0.05 wt %, 0.06 wt %, 0.07 wt %,0.08 wt %, 0.09 wt %, 0.1 wt %, 0.2 wt %, 0.3 wt %, 0.4 wt %, 0.5 wt %,0.6 wt %, 0.7 wt %, 0.8 wt %, 0.9 wt %, 1.0 wt %, 1.2 wt %, 1.3 wt %,1.4 wt %, 1.5 wt %, 1.6 wt %, 1.7 wt %, 1.8 wt %, 1.9 wt %, 2.0 wt %,2.1 wt %, 2.2 wt %, 2.3 wt %, 2.4 wt %, 2.5 wt %, 2.6 wt %, 2.7 wt %,2.8 wt %, 2.9 wt %, 3.0 wt %, 3.1 wt %, 3.2 wt %, 3.3 wt %, 3.4 wt %,3.5 wt %, 3.6 wt %, 3.7 wt %, 3.8 wt %, 3.9 wt % 4.0 wt % 4.1 wt %, 4.2wt %, 4.3 wt %, 4.4 wt %, 4.5 wt %, 4.6 wt %, 4.7 wt %, 4.8 wt %, 4.9 wt%, 5.0 wt % or any range encompassed by the foregoing values.

Examples of antioxidants that may be used in the present inventioninclude, but are not limited to, ascorbic acid, ascorbyl palmitate (AP),butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citricacid, ethyl oleate, fumaric acid, hypophosphorous acid, malic acid,monothioglycerol, potassium metabisulfite, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumsulfite, sodium thiosulfate, sulfur dioxide, tocopherols, methylparaben,ethylparaben, propylparaben, butylparaben, benzyl benzoate, pyridoxine,ethyl vanillin and mixtures thereof. Preferred antioxidants for useaccording to the invention include BHT, BHA, AP, propyl gallate, alphatocopherol, or any mixtures thereof. Generally, the amount antioxidantpresent in the composition of the present invention will comprise about0.0001 wt % to about 5 wt %, preferably about 0.01 wt % to about 2 wt %,and most preferably about 0.05 wt % to about 1 wt % based on the totalweight of the composition.

As used herein, and unless otherwise defined, the term “drying agent”refers to pharmaceutically acceptable excipients that have the abilityto bind or absorb water present in the composition. Examples of a dryingagent useful in the present invention may include, for example,magnesium oxide (MgO), aluminum oxide, attapulgite, bentonite, kaolin,pectin, saponite, colloidal silicon dioxide, and mixtures thereof.Depending upon the specific dosage form, the viscosity enhancing agentsdiscussed below may also be used as a drying agent. The amount of dryingagent, if present, in the composition of the present invention can rangefrom about 0.05 wt % to about 10 wt % of the total weight of thecomposition, preferably about 0.1 wt % to about 5 wt % of the totalweight of the composition, and most preferably about 0.5 wt % to about2.5 wt % of the total weight of the composition.

Examples of buffers that may be used in the present invention include,but are not limited to, acetic acid, adipic acid, ammonium carbonate,ammonium phosphate, boric acid, citric acid, lactic acid, phosphoricacid, potassium citrate, potassium phosphate, sodium acetate, sodiumcitrate, sodium carbonate, potassium carbonate, sodium bicarbonate,potassium bicarbonate, sodium lactate, sodium phosphate, succinic acid,and combinations thereof. Typically the buffer will comprise acombination of the foregoing as to create a buffer system such as citricacid and sodium citrate or acetic acid and sodium acetate.

Examples of pH adjusting agents that may be used in the presentinvention include, but are not limited to, any of the pharmaceuticallyacceptable acids or bases used to adjust the pH of pharmaceuticalcompositions. Examples of compounds typically used to adjust the pH ofpharmaceutical compositions include hydrochloric acid, citric acid,lactic acid, tartaric acid, glacial acetic acid, sodium hydroxide,potassium hydroxide, arginine, lysine, meglumine, triethanol amine, orcombinations thereof.

If employed, the buffer and/or pH adjusting agent may comprise about0.01 wt % to about 20 wt % of the composition, preferably about 0.1 wt %to about 10 wt % of the composition, and most preferably about 0.5 wt %to about 5 wt % of the composition.

Fillers, sometimes referred to as diluents, may also be used in thepresent invention and include water; sugars such as lactose, dextrose,sucrose, maltose, or microcrystalline cellulose; clays, and mixturesthereof. Generally, the amount filler present in the compositions of thepresent invention will comprise about 0 wt % to about 90 wt %,preferably about 0.01 wt % to about 80 wt %, and most preferably about 1wt % to about 70 wt % based on the total weight of the composition.

Viscosity enhancing agents that may be used in the present inventioninclude organic materials such as natural or synthetic waxes, C₁₂-C₆₀alcohols, C₁₂-C₆₀ acids, alpha-hydroxy fatty acids, polyhydroxy fattyacid esters, polyhydroxy fatty acid amides, and inorganic/organicmaterials such as metal ester complexes containing zinc, calcium,aluminum or magnesium, fumed silicas, and organoclays. Additionalviscosity enhancing agents include polyol polyesters, glyceryl esters,polyglyceryl esters, and polysiloxanes.

Waxes are also suitable for use as viscosity enhancing agents incompositions of the present invention. Natural waxes may include, butare not limited to, carnauba, ozokerite, beeswax, candelilla, paraffin,ceresin, esparto, ouricuri, rezowax and other known mined and mineralwaxes. Synthetic waxes may include, but are not limited to, paraffinwaxes and microcrystalline waxes.

Still further viscosity enhancing agents that may be included in thecompositions of the present invention are gelling agents. Gelling agentsare materials that can swell or expand when in contact with water.Examples of gelling agents that may be used in the present inventioninclude swellable polymers, also known as osmopolymers or hydrogels. Theswellable polymer can be non-cross-linked or lightly cross-linked. Thecross-links can be covalent or ionic bonds with the polymer possessingthe ability to swell in the presence of fluid, and when cross-linked, itwill not be dissolved in the fluid. The polymer can be of plant, animal,or synthetic origin. Polymeric gelling agents useful for the presentpurpose include polyhydroxyalkylcellulose having a molecular weightgreater than 50,000, such as hydroxyl propylmethylcellulose (METHOCEL K100M available from Dow Chemical); poly(hydroxyalkylmethacrylate) havinga molecular weight of from 5,000 to 5,000,000; poly(vinylpyrrolidone)having a molecular weight of from 100,000 to 3,000,000; anionic andcationic hydrogels; poly(electrolyte) complexes; poly(vinylalcohol)having a low acetate residual; a swellable mixture of agar andcarboxymethyl cellulose; a swellable composition comprising methylcellulose mixed with a sparingly cross-linked agar; a polyether having amolecular weight of from 10,000 to 6,000,000; a water-swellablecopolymer produced by a dispersion of a finely divided copolymer ofmaleic anhydride with styrene, ethylene, propylene, or isobutylene; awater-swellable polymer of N-vinyl lactams, and the like.

Other gelling agents useful in the present invention include pectinhaving a molecular weight ranging from 30,000 to 300,000;polysaccharides such as agar, acacia, karaya, tragacanth, algins andguar; CARBOPOL® an acrylic acid polymer, a carboxyvinyl polymer,sometimes referred to as carboxypolymethylene, a polymer of acrylic acidcross-linked with a polyallyl ether of sucrose, as described in U.S.Pat. Nos. 2,798,053 and 2,909,462 and available as CARBOPOL® 934, 940and 941, and its salt derivatives; polyacrylamides; water-swellableindene maleic anhydride polymers; GOOD-RITE® polyacrylic acid having amolecular weight of 80,000 to 200,000; POLYOX™ polyethylene oxidepolymers having a molecular weight of 100,000 to 7,000,000; starch graftcopolymers; AQUA-KEEP™ acrylate polymers with water absorbability ofabout 400 times its original weight; diesters of polyglucan; a mixtureof cross-linked polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone);poly(ethylene glycol) having a molecular weight of 4,000 to 100,000.Representative polymers possessing gelling properties are described inU.S. Pat. Nos. 6,419,954, 4,915,949, 4,327,725, 4,207,893 and inHandbook of Common Polymers, by Scott and Roff, published by ClevelandRubber Company, Cleveland, Ohio.

Generally, the amount of viscosity enhancing agent present in thecompositions of the present invention will comprise about 0 wt % toabout 30 wt %, preferably about 0.01 wt % to about 25 wt %, and mostpreferably about 1 wt % to about 15 wt % based on the total weight ofthe composition. In the semi-solid embodiments of the present invention,the viscosity enhancing agent that is a solid at ambient temperaturesbut that exhibits a melting point below 120° C., preferably below 100°C., more preferably below 80° C. and most preferably below 60° C. asdiscussed above and may comprise about 7.5 wt % to about 75 wt %,preferably about 10 wt % to about 60 wt % and most preferably about 12wt % to about 50 wt % of the total weight of the composition. Examplesof these viscosity enhancing agents include but are not limited to thenatural or synthetic waxes such as carnauba wax, cetyl ester wax,microcrystalline wax, white wax, yellow wax, bees wax, ozokerite,paraffin, ceresin, esparto, ouricuri, and rezowax, hard fats (akahydrogenated vegetable glycerides), hydrogenated vegetable oils, C₁₂-C₆₀alcohols, C₁₂-C₆₀ acids, alpha-hydroxy fatty acids, polyhydroxy fattyacid esters, polyhydroxy fatty acid amides and combinations thereofdescribed above.

Examples of binders that may be employed in the solid dosage form of thepresent invention include acacia, povidone, hypromellose, hydroxypropylcellulose, hydroxyethyl cellulose, polyethylene oxide,polymethacrylates, methyl cellulose, ethyl cellulose, pregelatinizedstarch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, thebinder is selected from povidone, hypromellose, hydroxypropyl cellulose,hydroxyethyl cellulose, polymethacrylates, methyl cellulose, gelatin andethyl cellulose, or mixtures thereof. Especially preferred bindersinclude water soluble binders such as povidone, hypromellose,hydroxypropyl cellulose, gelatin and mixtures thereof. If the binder isa polymeric binder, it is preferred that the binder have a low molecularweight and/or exhibit a viscosity of less than 200 mPa·s, preferablyless than 100 mPa·s, and most preferably less than 50 mPa·s when testedat a concentration of 2% (w/v) aqueous preparation at 20° C.

Generally, the amount binder present in the compositions of the presentinvention will comprise about 0 wt % to about 30 wt %, preferably about0.01 wt % to about 25 wt %, and most preferably about 1 wt % to about 15wt % based on the total weight of the composition.

Examples of disintegrants that may be employed in the solid dosage formof the present invention include croscarmellose sodium, starch,crospovidone, sodium starch glycolate, alginic acid, calciumcarboxymethylcellulose, sodium carboxymethylcellulose, potassiumcarboxymethylcellulose, powdered cellulose, chitosan, guar gum,magnesium aluminum silicate, methylcellulose, sodium alginate, andmixtures thereof. Generally, the amount of disintegrant present in thecompositions of the present invention will comprise about 0 wt % toabout 40 wt %, preferably about 1 wt % to about 25 wt %, and mostpreferably about 2 wt % to about 20 wt % based on the total weight ofthe composition.

Examples of lubricants that may be employed in the solid dosage form ofthe present invention include magnesium stearate, sodium stearylfumarate, stearic acid, glyceryl behenate, polyethylene glycols(preferably wherein the polyethylene glycol has a molecular weight of6000 or more), polyoxyethylene stearate, magnesium lauryl sulfate,sodium oleate, and mixtures thereof. The lubricants may be present in anamount ranging from about 0.1 wt % to about 10 wt % based on the totalweight of the dosage form, preferably about 0.2 wt % to about 7 wt %,and most preferably about 0.5 wt % to about 5 wt %.

Examples of glidants that may be employed in the solid dosage form ofthe present invention include colloidal silicon dioxide, corn starch,talc and mixtures thereof. The glidants may be present in an amountranging from about 0.1 wt % to about 10 wt % based on the total weightof the dosage form, preferably about 0.2 wt % to about 7 wt %, and mostpreferably about 0.5 wt % to about 5 wt %.

Examples of flavoring agents that may be employed in the solid dosageform of the present invention include artificial sweeteners such asaspartame, saccharin, dipotassium glycyrrhizinate, stevia, thaumatin,and flavorants such as citric acid, peppermint oil, wintergreen oil,menthol, lemon, lime, orange, grape, cherry, and vanilla extract.Additional taste enhancing agents are described in U.S. Pat. No.6,027,746 which is incorporated herein by reference.

Embodiment A of the present invention is an oral liquid dosage form,preferably in a hard or soft capsule comprising:

-   -   (i) about 1 wt % to about 80 wt %, preferably about 2 wt % to        about 70 wt %, more preferably about 3 wt % to about 60 wt % and        most preferably about 5 wt % to about 50 wt % of a KI C₈-C₁₆        aliphatic sulfate salt, preferably wherein the KI is selected        from the group consisting of acalabrutinib, afatinib, alectinib,        axitinib, bosutinib, brigatinib, cabozantinib, ceritinib,        cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib,        enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,        imatinib, lapatinib, lenvatinib, neratinib, nilotinib,        nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,        ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and        vemurafenib and most preferably from the group consisting of        afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib,        osimertinib, pazopanib and ponatinib and preferably wherein the        KI C₈-C₁₆ aliphatic sulfate salt is a KI lauryl sulfate salt and        most preferably a KI mono- or di-lauryl sulfate salt;    -   (ii) about 1 wt % to about 95 wt %, preferably about 5 wt % to        about 90 wt % and most preferably about 10 wt % to about 80 wt %        of a liquid carrier selected from the group consisting of fatty        acids, medium chain triglycerides, fatty acid esters, fatty acid        alcohols, vegetable oils such as corn oil, soy bean oil, olive        oil, sun flower oil, peanut oil or mixtures thereof; and    -   (iii) optionally one or more additional pharmaceutically        acceptable excipients selected from the group consisting of a        stabilizer, a filler, a viscosity enhancing agent, a binder, a        disintegrant, a lubricant, a glidant, a flavoring agent, and        combinations thereof.

Embodiment B of the present invention is an oral solid or semi-soliddosage form that may be a tablet, or hard or soft capsule comprising:

-   -   (i) about 1 wt % to about 80 wt %, preferably about 2 wt % to        about 70 wt %, more preferably about 3 wt % to about 60 wt % and        most preferably about 5 wt % to about 50 wt % of a KI C₈-C₁₆        aliphatic sulfate salt, preferably wherein the KI is selected        from the group consisting of acalabrutinib, afatinib, alectinib,        axitinib, bosutinib, brigatinib, cabozantinib, ceritinib,        cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib,        enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,        imatinib, lapatinib, lenvatinib, neratinib, nilotinib,        nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,        ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and        vemurafenib and most preferably from the group consisting of        afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib,        osimertinib, pazopanib and ponatinib and preferably wherein the        KI C₈-C₁₆ aliphatic sulfate salt is a KI lauryl sulfate salt and        most preferably a KI mono- or di-lauryl sulfate salt;    -   (ii) about 1 wt % to about 90 wt %, preferably about 2.5 wt % to        about 80 wt %, more preferably about 3 wt % to about 70 wt % and        most preferably about 5 wt % to about 60 wt % of a solid carrier        with a melting point between 25° C. and less than 120° C.,        preferably less than 100° C., more preferably less than 80° C.        and most preferably less than 60° C., and wherein the solid        carrier is preferably selected from the group consisting of        polyethylene glycol, hard fat, hydrogenate vegetable oil,        vitamin E polyethylene glycol succinate, wax, poloxamer and        combinations of the foregoing; and    -   (iii) optionally one or more additional pharmaceutically        acceptable excipients selected from the group consisting of a        stabilizer, a filler, a viscosity enhancing agent, a binder, a        disintegrant, a lubricant, a glidant, a flavoring agent, and        combinations thereof.

Embodiment C of the present invention is an oral dosage form, such as ahard or soft capsule comprising:

-   -   (i) about 1 wt % to about 80 wt %, preferably about 2 wt % to        about 70 wt %, more preferably about 3 wt % to about 60 wt % and        most preferably about 5 wt % to about 50 wt % of a KI C₈-C₁₆        aliphatic sulfate salt, preferably wherein the KI is selected        from the group consisting of acalabrutinib, afatinib, alectinib,        axitinib, bosutinib, brigatinib, cabozantinib, ceritinib,        cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib,        enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,        imatinib, lapatinib, lenvatinib, neratinib, nilotinib,        nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,        ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and        vemurafenib and most preferably from the group consisting of        afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib,        osimertinib, pazopanib and ponatinib and preferably wherein the        KI C₈-C₁₆ aliphatic sulfate salt is a KI lauryl sulfate salt and        most preferably a KI mono- or di-lauryl sulfate salt;    -   (ii) about 1 wt % to about 60 wt %, preferably about 2 wt % to        about 50 wt % and most preferably about 3 wt % to about 40 wt %        of at least one wetting agent, emulsifying agent, solubilizing        agent, surfactant or combinations thereof that exhibits an HLB        value of about 10 or greater, preferably about 11 or greater,        more preferably about 12 or greater and most preferably about 14        or greater and wherein the at least one wetting agent,        emulsifying agent, solubilizing agent, surfactant or        combinations thereof that exhibits an HLB value of about 10 or        greater is preferably selected from the group consisting of        fatty alcohol acid or amide ethoxylates, monoglyceride        ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides,        polyoxyethylene castor oil, polyoxyethylene hydrogenated castor        oil, poloxamer, tyloxapol, a fatty acid ester or fatty acid        alcohol of a polyglyceride or combinations thereof and most        preferably selected form the group consisting of polyoxyethylene        castor oil, polyoxyethylene hydrogenated castor oil, poloxamer,        a caprylic/capric triglyceride or combinations thereof;    -   (iii) about 5 wt % to about 90 wt %, preferably about 10 wt % to        about 85 wt % and most preferably about 15 wt % to about 80 wt %        of a secondary carrier with an HLB value of about less than 10,        preferably about 9 or less, about 8 or less and most preferably        about 7 or less and wherein the secondary carrier is selected        form the group consisting of a wetting agent, an emulsifying        agent, a solubilizing agent, a surfactant or combinations        thereof with an HLB value of about less than 10 and more        preferably is selected from the group consisting of medium chain        monoglycerides, medium chain diglycerides, polyoxylglycerides,        sorbitan esters, sorbitan fatty acid esters, phospholipids and        combinations thereof and most preferably medium chain        monoglycerides, medium chain diglycerides, lecithins and        combinations; and    -   (iv) optionally one or more additional pharmaceutically        acceptable excipients selected from the group consisting of a        stabilizer, a filler, a viscosity enhancing agent, a binder, a        disintegrant, a lubricant, a glidant, a flavoring agent, and        combinations thereof.

In certain embodiments of the capsule dosage form, the at least onewetting agent, emulsifying agent, solubilizing agent, surfactant orcombinations thereof that exhibits an HLB value of about 10 or greaterand the secondary carrier with an HLB value of about less than 10 areliquids at 25° C. and the KI salt, at least one wetting agent,emulsifying agent, solubilizing agent, surfactant or combinationsthereof that exhibits an HLB value of about 10 or greater and thesecondary carrier with an HLB value of about less than 10 are anintimate mixture.

Embodiment D of the present invention is an oral solid dosage form suchas a tablet or capsule wherein the tablet or contents of the capsulecomprises:

-   -   (i) about 1 wt % to about 80 wt %, preferably about 2 wt % to        about 70 wt %, more preferably about 3 wt % to about 60 wt % and        most preferably about 5 wt % to about 50 wt % of a KI C₈-C₁₆        aliphatic sulfate salt, preferably wherein the KI is selected        from the group consisting of acalabrutinib, afatinib, alectinib,        axitinib, bosutinib, brigatinib, cabozantinib, ceritinib,        cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib,        enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,        imatinib, lapatinib, lenvatinib, neratinib, nilotinib,        nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,        ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and        vemurafenib and most preferably from the group consisting of        afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib,        osimertinib, pazopanib and ponatinib and preferably wherein the        KI C₈-C₁₆ aliphatic sulfate salt is a KI lauryl sulfate salt and        most preferably a KI mono- or di-lauryl sulfate salt;    -   (ii) about 1 wt % to about 60 wt %, preferably about 2 wt % to        about 50 wt % and most preferably about 3 wt % to about 40 wt %        of one or more wetting agents, solubilizing agents, emulsifying        agents, surfactants or combination thereof that exhibits an HLB        value of about 10 or greater, preferably an HLB value of about        11 or greater, more preferably about 12 or greater, and most        preferably about 14 or greater wherein the one or more wetting        agents, emulsifying agents, solubilizing agents, surfactants or        combinations thereof with an HLB value of about 10 or greater is        selected from the group consisting of fatty alcohol acid or        amide ethoxylates, monoglyceride ethoxylates, sorbitan ester        ethoxylates alkyl polyglycosides, polyoxyethylene castor oil,        polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, a        fatty acid ester or fatty acid alcohol of a polyglyceride or        combinations thereof and most preferably selected form the group        consisting of polyoxyethylene castor oil, polyoxyethylene        hydrogenated castor oil, poloxamer, a caprylic/capric        triglyceride or combinations thereof;    -   (iii) about 0 wt % to about 40 wt %, preferably about 1 wt % to        about 25 wt % and most preferably about 2.5 wt % to about 20 wt        % of a disintegrant;    -   (iv) about 5 wt % to about 90 wt %, preferably about 15 wt % to        about 85 wt % and most preferably about 20 wt % to about 80 wt %        of a filler; and    -   (v) optionally one or more additional pharmaceutically        acceptable excipients selected from the group consisting of a        stabilizer, a viscosity enhancing agent, a binder, a lubricant,        a glidant, a flavoring agent, and combinations thereof.

In certain embodiments of Embodiment D, the KI C₈-C₁₆ aliphatic sulfatesalt and at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95% or 100% of the total amount of the one or morewetting agents, emulsifying agents, solubilizing agents, surfactants orcombinations thereof with an HLB value of about 10 or greater arepresent in the solid tablet or solid capsule in an intimate mixture,preferably formed before being combined with the elements (iii), (iv)and/or (v).

Embodiment E of the present invention is an oral semi-solid compositioncomprising:

-   -   (i) about 1 wt % to about 80 wt %, preferably about 2 wt % to        about 70 wt %, more preferably about 3 wt % to about 60 wt % and        most preferably about 5 wt % to about 50 wt % of a KI C₈-C₁₆        aliphatic sulfate salt, preferably wherein the KI is selected        from the group consisting of acalabrutinib, afatinib, alectinib,        axitinib, bosutinib, brigatinib, cabozantinib, ceritinib,        cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib,        enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,        imatinib, lapatinib, lenvatinib, neratinib, nilotinib,        nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,        ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and        vemurafenib and most preferably from the group consisting of        afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib,        osimertinib, pazopanib and ponatinib and preferably wherein the        KI C₈-C₁₆ aliphatic sulfate salt is a KI lauryl sulfate salt and        most preferably a KI mono- or di-lauryl sulfate salt;    -   (ii) about 1 wt % to about 70 wt %, preferably about 2 wt % to        about 60 wt % and most preferably about 5 wt % to about 50 wt %        of one or more wetting agents, solubilizing agents, emulsifying        agents, surfactants or combination thereof that exhibits an HLB        value of about 10 or greater, preferably an HLB value of about        11 or greater, more preferably about 12 or greater, and most        preferably about 14 or greater wherein the one or more wetting        agents, emulsifying agents, solubilizing agents, surfactants or        combinations thereof with an HLB value of about 10 or greater is        selected from the group consisting of fatty alcohol acid or        amide ethoxylates, monoglyceride ethoxylates, sorbitan ester        ethoxylates alkyl polyglycosides, polyoxyethylene castor oil,        polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, a        fatty acid ester or fatty acid alcohol of a polyglyceride or        combinations thereof and most preferably selected form the group        consisting of polyoxyethylene castor oil, polyoxyethylene        hydrogenated castor oil, poloxamer, a caprylic/capric        triglyceride or combinations thereof;    -   (iii) about 1 wt % to about 70 wt %, preferably about 2 wt % to        about 60 wt % and most preferably about 5 wt % to about 50 wt %        of a secondary carrier with an HLB value of about less than 10,        preferably about 9 or less, about 8 or less and most preferably        about 7 or less and wherein the secondary carrier is selected        form the group consisting of a wetting agent, an emulsifying        agent, a solubilizing agent, a surfactant or combinations        thereof with an HLB value of about less than 10 and more        preferably is selected from the group consisting of medium chain        monoglycerides, medium chain diglycerides, polyoxylglycerides,        sorbitan esters, sorbitan fatty acid esters, phospholipids and        combinations thereof and most preferably medium chain        monoglycerides, medium chain diglycerides, lecithin and        combinations;    -   (iv) about 0.5 wt % to about 70 wt %, preferably about 1 wt % to        about 60 wt % and most preferably about 2.5 wt % to about 50 wt        % of a viscosity enhancing agent that is a solid at ambient        temperature but exhibits a melting point below 120° C.,        preferably below 100° C., more preferably below 80° C. and most        preferably below 60° C. where in the viscosity enhancing agent        is selected from the group consisting of natural or synthetic        waxes such as carnauba wax, cetyl ester wax, microcrystalline        wax, white wax, yellow wax, bees wax, ozokerite, paraffin,        ceresin, esparto, ouricuri, and rezowax, hard fats (aka        hydrogenated vegetable glycerides), hydrogenated vegetable oils,        C₁₂-C₆₀ alcohols, C₁₂-C₆₀ acids, alpha-hydroxy fatty acids,        polyhydroxy fatty acid esters, polyhydroxy fatty acid amides and        combinations thereof; and    -   (v) optionally one or more additional pharmaceutically        acceptable excipients selected from the group consisting of a        stabilizer, a binder, a lubricant, a glidant, a flavoring agent,        and combinations thereof;        -   wherein the KI C₈-C₁₆ aliphatic sulfate salt and the one or            more wetting agents, emulsifying agents, solubilizing            agents, surfactants or combinations thereof with an HLB            value of about 10 or greater are present in an intimate            mixture.

Embodiment F of the present invention is an oral solid dosage form suchas a tablet or capsule wherein the tablet or contents of the capsulecomprises a solid dispersion comprising:

-   -   (i) about 1 wt % to about 80 wt %, preferably about 2 wt % to        about 70 wt %, more preferably about 3 wt % to about 60 wt % and        most preferably about 5 wt % to about 50 wt % of a KI C₈-C₁₆        aliphatic sulfate salt, preferably wherein the KI is selected        from the group consisting of acalabrutinib, afatinib, alectinib,        axitinib, bosutinib, brigatinib, cabozantinib, ceritinib,        cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib,        enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,        imatinib, lapatinib, lenvatinib, neratinib, nilotinib,        nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,        ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and        vemurafenib and most preferably from the group consisting of        afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib,        osimertinib, pazopanib and ponatinib and preferably wherein the        KI C₈-C₁₆ aliphatic sulfate salt is a KI lauryl sulfate salt and        most preferably a KI mono- or di-lauryl sulfate salt;    -   (ii) about 1 wt % to about 60 wt %, preferably about 2 wt % to        about 50 wt % and most preferably about 3 wt % to about 40 wt %        of one or more wetting agents, solubilizing agents, emulsifying        agents, surfactants or combination thereof that exhibits an HLB        value of about 10 or greater, preferably an HLB value of about        11 or greater, more preferably about 12 or greater, and most        preferably about 14 or greater wherein the one or more wetting        agents, emulsifying agents, solubilizing agents, surfactants or        combinations thereof with an HLB value of about 10 or greater is        selected from the group consisting of fatty alcohol acid or        amide ethoxylates, monoglyceride ethoxylates, sorbitan ester        ethoxylates alkyl polyglycosides, polyoxyethylene castor oil,        polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, a        fatty acid ester or fatty acid alcohol of a polyglyceride or        combinations thereof and most preferably selected form the group        consisting of polyoxyethylene castor oil, polyoxyethylene        hydrogenated castor oil, poloxamer, a caprylic/capric        triglyceride or combinations thereof; and    -   (iii) about 1 wt % to about 60 wt %, preferably about 2 wt % to        about 50 wt % and most preferably about 3 wt % to about 45 wt %        of one or more polymeric agents, preferably water soluble        polymeric agents that exhibit a viscosity of less than 200        mPa□s, preferably less than 100 mPa□s, and most preferably less        than 50 mPa□s when tested at a concentration of 2% (w/v) aqueous        preparation at 20° C. and most preferably wherein the polymeric        agent is selected from the group consisting of povidone,        hypromellose, hydroxypropyl cellulose, gelatin and mixtures        thereof.

The solid dispersion dosage form of Embodiment F may further comprisewithin the solid dispersion or mixed with the solid dispersion, i.e.,extra granular,

-   (iv) about 0 wt % to about 40 wt %, preferably about 1 wt % to about    25 wt % and most preferably about 2.5 wt % to about 20 wt % of a    disintegrant;-   (v) about 0 wt % to about 90 wt %, preferably about 15 wt % to about    85 wt % and most preferably about 20 wt % to about 80 wt % of a    filler; and-   (vi) optionally one or more additional pharmaceutically acceptable    excipients selected from the group consisting of a stabilizer, a    viscosity enhancing agent, a binder, a lubricant, a glidant, a    flavoring agent, and combinations thereof.

Embodiment G of the present invention is a sustained or controlledrelease oral solid dosage form such as a tablet or capsule wherein thetablet or contents of the capsule comprises:

-   (i) about 1 wt % to about 80 wt %, preferably about 2 wt % to about    70 wt %, more preferably about 3 wt % to about 60 wt % and most    preferably about 5 wt % to about 50 wt % of a KI C₈-C₁₆ aliphatic    sulfate salt, preferably wherein the KI is selected from the group    consisting of acalabrutinib, afatinib, alectinib, axitinib,    bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib,    crizotinib, dabrafenib, dasatinib, defactinib, enasidenib,    erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib,    lenvatinib, neratinib, nilotinib, nintedanib, osimertinib,    pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib,    sunitinib, trametinib, vandetanib, and vemurafenib and most    preferably from the group consisting of afatinib, dasatinib,    erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib    and ponatinib and preferably wherein the KI C₈-C₁₆ aliphatic sulfate    salt is a KI lauryl sulfate salt and most preferably a KI mono- or    di-lauryl sulfate salt;-   (ii) about 1 wt % to about 60 wt %, preferably about 2 wt % to about    50 wt % and most preferably about 3 wt % to about 40 wt % of one or    more wetting agents, solubilizing agents, emulsifying agents,    surfactants or combination thereof that exhibits an HLB value of    about 10 or greater, preferably an HLB value of about 11 or greater,    more preferably greater than 12 and most preferably about 14 or    greater wherein the one or more wetting agents, emulsifying agents,    solubilizing agents, surfactants or combinations thereof with an HLB    value of about 10 or greater is selected from the group consisting    of fatty alcohol acid or amide ethoxylates, monoglyceride    ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides,    polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil,    poloxamer, tyloxapol, a fatty acid ester or fatty acid alcohol of a    polyglyceride or combinations thereof and most preferably selected    form the group consisting of polyoxyethylene castor oil,    polyoxyethylene hydrogenated castor oil, poloxamer, a    caprylic/capric triglyceride or combinations thereof;-   (iii) about 0.5 wt % to about 50 wt %, preferably about 1 wt % to    about 40 wt % and most preferably about 2 wt % to about 35 wt % of a    controlled or sustained agent, wherein the controlled or sustained    release agent is an excipient that controls or sustains the release    of the KI C₈-C₁₆ aliphatic sulfate salt from the dosage form for a    period of time greater than one hour, greater than two hours,    greater than 3 hours, greater than 4 hours, greater than 5 hours, or    greater than six hours and preferably is selected from the viscosity    enhancing agents described previously and more preferably is gelling    agent as previously described and may be selected from the group    consisting of a polyhydroxyalkylcellulose having a molecular weight    greater than 50,000, such as hydroxyl propylmethylcellulose    (METHOCEL K 100M available from Dow Chemical); a    poly(hydroxyalkylmethacrylate) having a molecular weight of from    5,000 to 5,000,000; a poly(vinylpyrrolidone) having a molecular    weight of from 100,000 to 3,000,000; pectin having a molecular    weight ranging from 30,000 to 300,000; a polysaccharide such as    agar, acacia, karaya, tragacanth, algins and guar; an acrylic acid    polymer (CARBOPOL®); a polyethylene oxide polymer (POLYOX™) having a    molecular weight of 100,000 to 7,000,000 and combinations thereof;-   (iv) optionally about 5 wt % to about 90 wt %, preferably about 15    wt % to about 85 wt % and most preferably about 20 wt % to about 80    wt % of a filler; and-   (v) optionally one or more additional pharmaceutically acceptable    excipients selected from the group consisting of a stabilizer, a    binder, a lubricant, a glidant, a flavoring agent, and combinations    thereof.

In certain embodiments of Embodiment G, the KI C₈-C₁₆ aliphatic sulfatesalt and at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95% or 100% of the total amount of the one or morewetting agents, emulsifying agents, solubilizing agents, surfactants orcombinations thereof with an HLB value of about 10 or greater arepresent in the solid tablet or solid capsule in an intimate mixture,preferably formed before being combined with the elements (iii), (iv)and/or (v).

In certain embodiments of Embodiment G, the sustained or controlledrelease oral solid dosage form will release the KI C₈-C₁₆ aliphaticsulfate salt when tested using a USP Type II Apparatus (Paddle) with 900ml of an aqueous media with a pH of 6.8 and 0.1% sodium lauryl sulfiteat 75 rpm with or without a sinker as follows:

Time More Most (hour) Preferred Preferred Preferred 2  0-40%  0-35% 0-30% 4 5%-70% 7.5%-60%  10%-50%  6 10%-100% 15%-100% 20%-100% 10 NLT*45% NLT 50% NLT 55% 12 NLT 50% NLT 60% NLT 70% *NLT = Not Less Than

In certain embodiments of the present invention and specificallyEmbodiments A-F, the oral solid dosage form will release the KI C₈-C₁₆aliphatic sulfate salt when tested using a USP Type II Apparatus(Paddle) with 500 ml of 0.1 N HCl at 75 rpm, with or without a sinkerand 37° C. as follows:

Time More Most (minutes) Preferred Preferred Preferred 15  0-50% 5%-50%10%-50% 30 10%-70%  25%-70%  35%-70% 45 35%-100% 45%-100%  50%-100% 60NLT 80% NLT 85% NLT 90%

Certain embodiments of the present invention and specifically the liquidoral dosage forms will release the KI C₈-C₁₆ aliphatic sulfate salt whentested using a USP Type II Apparatus (Paddle) with 500-900 ml of 0.1 NHCl at 75 rpm, with or without a sinker and 37° C. as follows:

Time More Most (minutes) Preferred Preferred Preferred 15    0-50% 5%-50% 10%-50% 30  5%-70% 10%-60% 10%-55% 60 10%-80% 15%-80% 20%-80%120 NLT 35% NLT 40% NLT 45%

Alternatively certain embodiments of the present invention andspecifically the liquid oral dosage forms will release the KI C₈-C₁₆aliphatic sulfate salt when tested using a USP Type II Apparatus(Paddle) with 900 ml of 0.1 N HCl and 0.1% Tween 80 at 75 rpm, with orwithout a sinker and 37° C. as follows:

Time More Most (minutes) Preferred Preferred Preferred 15    5-50%10%-50% 15%-50% 30 10%-85% 15%-80% 20%-75% 60 40%-95% 45%-95% 50%-95%120 NLT 70% NLT 80% NLT 85%

The compositions and dosage forms of the present invention andspecifically the compositions and dosage forms described above inEmbodiments A-G will be stable when prepared and stored under normal andaccelerated conditions. More specifically, the dosage forms of thepresent invention will contain about 1.0% or less of any individualdegradation product, preferably about 0.75% or less of any individualdegradation product, and most preferably about 0.5% or less of anyindividual degradation product when the dosage form is stored in asealed bottle, preferably a sealed plastic bottle such as a high densitypolyethylene bottle (with or without a desiccant), at approximately 25°C. and approximately 60% relative humidity for at least three months,preferably at least six months and most preferably at least one yearand/or at approximately 40° C. and approximately 75% relative humidityfor one month, two months, or three months.

The compositions and dosage forms of the present invention andspecifically the compositions and dosage forms described above inEmbodiments A-G should also contain a total amount of degradationproducts of about 2.0% or less, preferably about 1.5% or less, and mostpreferably about 1.0% or less when the dosage form is stored in a sealedbottle, preferably a sealed plastic bottle such as a high densitypolyethylene bottle (with or without a desiccant) at approximately 25°C. and approximately 60% relative humidity for at least three months,preferably at least six months, and most preferably at least one yearand/or at approximately 40° C. and approximately 75% relative humidityfor one month, two months, or three months.

KI C₈-C₁₆ aliphatic sulfate salt and specifically the KI lauryl sulfatesalt employed in the compositions and dosage forms of the presentinvention and specifically the compositions and dosage forms describedabove in Embodiments A-G can be in an amorphous or crystalline form. TheKI C₈-C₁₆ aliphatic sulfate salt and specifically the KI lauryl sulfatesalt employed the solid dispersion dosage forms of Embodiment F willpreferably be in an amorphous form.

Table 1 shows the amount of some KI lauryl sulfate salts that will bepresent in the dosage forms of the present invention and specificallythe dosage forms described above in Embodiments A-G:

TABLE 1 Amount of KI free base per dosage unit KI Preferred MorePreferred Most Preferred acalabrutinib lauryl sulfate 25-400 50-35075-300 afatinib lauryl sulfate  5-200 7.5-150  10-100 alectinib laurylsulfate 25-400 50-350 75-300 axitinib lauryl sulfate 0.25-20   0.5-15 0.75-10   bosutinib lauryl sulfate 35-500 40-500 50-500 brigatiniblauryl sulfate 10-300 20-250 25-200 cabozantinib lauryl sulfate  5-20010-150 15-100 ceritinib lauryl sulfate 25-400 50-350 75-300 cobimetiniblauryl sulfate 5-50 10-40  15-30  crizotinib lauryl sulfate 75-500100-400  150-300  dabrafenib lauryl sulfate 10-200 25-150 30-100dasatinib lauryl sulfate  5-250 10-175 15-150 enasidenib lauryl sulfate10-200 25-175 30-150 erlotinib lauryl sulfate  5-250 10-200 15-175fostamatinib lauryl sulfate 50-250 75-200 80-175 gefitinib laurylsulfate 100-400  150-350  200-300  ibrutinib lauryl sulfate 25-65050-600 60-575 imatinib lauryl sulfate 50-600 70-650 80-500 lapatiniblauryl sulfate 100-400  150-350  200-300  lenvatinib lauryl sulfate0.25-20   0.5-15  0.75-10   neratinib lauryl sulfate 10-100 15-80 25-75  nilotinib lauryl sulfate 10-400 15-350 25-300 nintedanib laurylsulfate 25-300 50-250 75-200 osimertinib lauryl sulfate 10-175 25-15030-100 pazopanib lauryl sulfate 50-600 100-500  150-450  ponatiniblauryl sulfate 2.5-100  5-75 10-50  regorafenib lauryl sulfate 10-10015-80  25-75  ruxolitinib lauryl sulfate 1-50 2-40 3-30 sorafenib laurylsulfate 50-400 100-300  150-250  sunitinib lauryl sulfate 2.5-100  5-7510-50  trametinib lauryl sulfate 0.25-10   0.3-7.5  0.4-5   vandetaniblauryl sulfate 50-500 75-400 80-350 vemurafenib lauryl sulfate 100-500 150-400  200-300 

Table 2 shows the U.S. FDA approved indications for the preferred KIcompounds and the conditions which the KI C₈-C₁₆ aliphatic sulfate saltsand specifically the KI lauryl sulfate salts of the present inventionmay be used to treat:

TABLE 2 KI U.S. FDA Approved Treatments acalabrutinib non-Hodgkinlymphoma (i.e., mantle cell lymphoma) afatinib non-small cell lungcarcinoma (NSCLC) alectinib non-small cell lung carcinoma (NSCLC)axitinib renal cell carcinoma bosutinib chronic myelogenous leukemia.brigatinib non-small cell lung carcinoma (NSCLC) cabozantinib thyroidcancer; renal cell carcinoma; and hepatocellar carcinoma ceritinibnon-small cell lung carcinoma (NSCLC) cobimetinib melanoma crizotinibnon-small cell lung carcinoma (NSCLC) dabrafenib melanoma dasatinibchronic myeloid leukemia (CML); acute lymphoblastic leukemia (ALL)enasidenib acute myeloid leukemia erlotinib non-small cell lungcarcinoma (NSCLC); pancreatic cancer fostamatinib thrombocytopeniagefitinib non-small cell lung carcinoma (NSCLC) ibrutinib mantle celllymphoma (MCL); chronic lymphocytic leukemia (CLL)/small lymphocyticlymphoma (SLL); Waldenström's macroglobulinemia (WM); marginal zonelymphoma (MZL); and chronic graft versus host disease (cGVHD) imatinibchronic myeloid leukemia; acute lymphoblastic leukemia;myelodysplastic/myeloproliferative diseases; aggressive systemicmastocytosis (ASM); hypereosinophilic syndrome (HES) and/or chroniceosinophilic leukemia (CEL); dermatofibrosarcoma protuberans (DFSP);gastrointestinal stromal tumors (GIST) lapatinib breast cancerlenvatinib differentiated thyroid cancer (DTC); renal cell carcinoma(RCC); hepatocellular carcinoma (HCC) neratinib breast cancer nilotinibchronic myeloid leukemia (CML) nintedanib idiopathetic pulmonaryfibrosis osimertinib non-small cell lung carcinoma (NSCLC) pazopanibadvanced renal cell carcinoma; advanced soft tissue sarcoma ponatinibchronic myeloid leukemia (CML); acute lymphoblastic leukemia (ALL)regorafenib metastatic colorectal cancer (CRC); gastrointestinal stromaltumor (GIST); hepatocellular carcinoma (HCC) ruxolitinib intermediate orhigh-risk myelofibrosis; polycythemia vera; steroid- refractory acutegraft-versus-host disease sorafenib hepatocellular carcinoma; advancedrenal cell carcinoma; differentiated thyroid carcinoma sunitinibgastrointestinal stromal tumor; advanced renal cell carcinoma trametinibmelanoma; non-small cell lung cancer (NSCLC); anaplastic thyroid cancer(ATC) vandetanib medullary thyroid cancer vemurafenib melanoma; ErdheimChester Disease

The present invention includes methods for treating the variousconditions identified in Table 2 by orally administering one or moredosage forms comprising a KI C₈-C₁₆ aliphatic sulfate salts andpreferably one or more dosage forms comprising a KI lauryl sulfate salt.In certain embodiments: (i) the oral administration may be with orwithout food and the oral administration will exhibit substantiallyconstant pharmacokinetic values or will not exhibit a food effect asdescribed in detail below; (ii) the oral administration will allow for areduction in the total daily dose of KI compared to the currently U.S.FDA approved KI compositions while maintaining similar pharmacokineticsas described in detail below; (iii) the oral administration may be withor without the co-administration of a gastric acid reducing agent andthe oral administration will not exhibit a gastric acid reducing agenteffect as described in detail below; or (iv) the oral administrationwill exhibit a combination of (i); (ii) and/or (iii).

In certain embodiments, the present invention includes methods fortreating the conditions identified in Table 2 by orally administeringone or more dosage forms described in Embodiments A-G and comprising aKI lauryl sulfate salt within the amounts recited in Table 1. In theseembodiments: (i) the oral administration may be with or without food andthe oral administration will exhibit substantially constantpharmacokinetic values or will not exhibit a food effect as described indetail below; (ii) the oral administration will allow for a reduction inthe total daily dose of KI compared to the currently U.S. FDA approvedKI compositions while maintaining similar pharmacokinetics as describedin detail below; (iii) the oral administration may be with or withoutthe co-administration of a gastric acid reducing agent and the oraladministration will not exhibit a gastric acid reducing agent effect asdescribed in detail below; or (iv) the oral administration will exhibita combination of (i); (ii) and/or (iii).

For example, a dosage form as described in Embodiments A-G andcomprising 10-400 mg of nilotinib lauryl sulfate, preferably 15-350 mgand more preferably 25-300 mg can be orally administered to a patient totreat chronic myeloid leukemia wherein (i) the oral administration maybe with or without food and the oral administration will not exhibit afood effect; (ii) the oral administration will allow for a reduction inthe total daily dose of nilotinib free base compared to the currentlyapproved dosing for nilotinib hydrochloride while maintaining similarpharmacokinetics as the oral administration of nilotinib hydrochloride;and (iii) the oral administration may be with or without theco-administration of a gastric acid reducing agent and the oraladministration will not exhibit a gastric acid reducing agent effect.

Similarly, a dosage form as described in Embodiments A-G and comprising5-250 mg of dasatinib lauryl sulfate, preferably 10-175 mg and morepreferably 15-150 mg can be orally administered to a patient to treatchronic myeloid leukemia and/or acute lymphoblastic leukemia wherein (i)the oral administration may be with or without food and the oraladministration will not exhibit a food effect; and (ii) the oraladministration may be with or without the co-administration of a gastricacid reducing agent and the oral administration will not exhibit agastric acid reducing agent effect.

The compositions and dosage forms of the present invention, includingbut not limited to Embodiments A-G, can be administered to a subject,wherein the subject may be either in a fed state or a fasted state andthe administration will under either fed or fasted conditions willresult in substantially constant pharmacokinetic values or no foodeffect. In general, a fed state is defined as having consumed foodwithin about 30 minutes prior to administration of the composition ordosage form. The food may be a high fat meal, a low fat meal, a highcalorie meal, or a low calorie meal. A fasted state may be defined asnot having ingested food for at least 10 hours prior to administrationof the composition or dosage form. In some embodiments, the subject mayhave fasted for at least 10 hours prior to administration and refrainsfrom ingesting food for about 30 minutes to 2 hours, preferably aboutone hour following administration. In other embodiments, the fastedsubject may not have ingested food for at least 1 hour, 2 hours, 3hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hoursprior to administration of each dose of the composition or dosage form.

The method of orally administering the composition and/or dosage form ofthe present invention, including but not limited to Embodiments A-G, toa patient or healthy subject will produce substantially constantpharmacokinetic values such as T_(max), C_(max) and AUC whether thecomposition is administered with or without food. A substantiallyconstant pharmacokinetic value means the measured pharmacokinetic valueobtained after a single or multiple dose administration of thecomposition or dosage form, including but not limited to EmbodimentsA-G, to a patient or healthy subject under fasting conditions asdescribed by the U.S. FDA Guidance documents does not change by morethan 40%, preferably does not change by more than 30% and mostpreferably does not change by more than 20% when the same composition isadministered to the same patient or healthy subject under fed conditionsas described in the U.S. FDA Guidance documents. For example, if aT_(max) of 3 hours was obtained after a single dose administration to apatient under fasting conditions, a T_(max) in the range of 1.8 hours to4.2 hours would be considered substantially constant, i.e., 3 hours±40%.

In certain preferred embodiments of the present invention, a single oraldose administration of a composition or dosage form prepared inaccordance with the present invention, including but not limited toEmbodiment A-G will be bioequivalent when administered under fed andfasting conditions or exhibit no food effect. The terms “bioequivalent”and “no food effect” are used in accordance with the U.S. FDA Guidancedocuments.

In certain embodiments of the present invention, a single oraladministration of the composition or dosage form prepared in accordancewith the present invention, including but not limited to EmbodimentsA-G, will produce a ratio of the KI C_(max) administered with food tothe KI C_(max) administered without food (C_(max fed)/C_(max fast)) ofabout 0.60 to about 2.5, preferably about 0.70 to about 2.0, morepreferably about 0.75 to about 1.5 and most preferably about 0.8 toabout 1.25. Similarly, in certain embodiments of the present invention,a single oral administration of the composition or dosage form preparedin accordance with the present invention, including but not limited toEmbodiments A-G will produce a ratio of the KI AUC_(0-∞) of thepharmaceutical composition administered with food to the KI AUC_(0-∞) ofthe pharmaceutical composition administered without food(AUC_(0-∞ fed)/AUC_(0-∞ fast)) of about 0.60 to about 2.5, preferablyabout 0.70 to about 2.0, more preferably about 0.75 to about 1.5 andmost preferably about 0.8 to about 1.25.

Upon oral administration of the compositions or dosage forms of thepresent invention, including but not limited to Embodiments A-G, a KIplasma profile is obtained wherein at least one pharmacokineticparameter differs by less than about 40% under fed and fastedconditions. In various embodiments, the pharmacokinetic parameter mayvary by less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5% under fedand fasted conditions. The pharmacokinetic parameter that is independentof food may be, but is not limited to, C_(max), AUC, T_(max), orcombinations thereof.

Certain embodiments of the present invention include methods fortreating cancer in human patients comprising the step of orallyadministering to the patient one or more dosage forms as described inEmbodiments A-G wherein the administration may be with or without foodand wherein the dose of the KI C₈-C₁₆ aliphatic sulfate salts andparticularly the KI lauryl sulfate does not require an adjustment indose or a change in time of administration.

In certain embodiments, the administration of compositions or dosageforms prepared in accordance with the present invention allow for areduction in the amount of KI base currently approved by the U.S. FDAand still obtain an equivalent therapeutic level. More specifically, thecompositions of the present invention will allow at least a 10%, 15%,20%, 25%, 30%, 35% 40%, 45% or 50% reduction in the daily amount ofacalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib,defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib,osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib,sunitinib, trametinib, vandetanib, or vemurafenib and still provideequivalent therapeutic levels, i.e., equivalent plasma levels.

Table 3 shows the currently U.S. FDA approved dosing for some of thepreferred KIs:

TABLE 3 U.S. FDA U.S. FDA Approved Form Recommended Daily KI (free baseamount) Dose acalabrutinib hydrochloride 150 mg capsule 1200 mg afatinib dimaleate 20 mg, 30 mg and 40 mg tablets 40 mg alectinibhydrochloride 150 mg capsule 600 mg  axitinib free base 1 mg and 5 mgtablet 10 mg-20 mg bosutinib free base 100 mg, 400 mg and 500 mg tablet100 mg-600 mg brigatinib free base 30 mg, 90 mg and 180 mg tablet  90mg-180 mg cabozantinib (S) malate 20 mg and 80 mg capsule and 20 mg,  60mg-180 mg 40 mg and 60 mg tablet ceritinib free base 150 mg capsule 150mg-450 mg cobimetinib fumarate 20 mg tablet 60 mg crizotinib 200 mg and250 mg capsule 200 mg-500 mg dabrafenib mesylate 50 mg and 75 mg capsule100 mg-300 mg dasatinib free base 20 mg, 50 mg, 70 mg, 80 mg, 100  70mg-140 mg mg and 140 mg tablet enasidenib mesylate 50 mg and 100 mgtablet  50 mg-100 mg erlotinib hydrochloride 25 mg, 100 mg and 150 mg100 mg-150 mg fostamatinib disodium 100 mg and 150 mg tablet 100 mg-300mg gefitinib free base 250 mg tablet 250 mg-500 mg ibrutinib free base70 mg and 140 mg capsule and 140  70 mg-560 mg mg 280 mg, 420 mg and 560mg tablet imatinib mesylate 100 mg and 400 mg tablets 300 mg-800 mglapatinib ditosylate 250 mg tablet 1,250 mg-1,500 mg lenvatinib mesylate4 mg and 10 mg capsule 10 mg-24 mg neratinib maleate 40 mg tablet  80mg-240 mg nilotinib hydrochloride 50 mg, 150 mg and 200 mg capsule 600mg-800 mg nintedanib esylate 100 mg and 150 mg capsule 100 mg-300 mgosimertinib mesylate 40 mg and 80 mg tablet 80 mg pazopanibhydrochloride 200 mg and 400 mg tablet 200 mg-800 mg ponatinibhydrochloride 15 mg, 30 mg and 45 mg tablet 30 mg-45 mg regorafenib freebase 40 mg tablet  80 mg-160 mg ruxolitinib phosphate 5 mg, 10 mg, 15mg, 20 mg and 25 10 mg-40 mg mg tablet sorafenib tosylate 200 mg tablet800 mg  sunitinib malate 12.5 mg, 25 mg, 37.5 mg and 50 mg 37.5 mg-50mg  capsule trametinib dimethyl sulfoxide 0.5 mg, 1 mg and 2 mg tablet 1mg-2 mg vandetanib free base 100 mg and 300 mg tablet 100 mg-300 mgvemurafenib free base 240 mg tablet 480 mg-960 mg

In certain embodiments, the oral administration of the KI C₈-C₁₆aliphatic sulfate salt of the present invention and specifically the KIlauryl sulfate salt, will allow at least a 10%, 15%, 20%, 25%, 30%, 35%40%, 45% or 50% reduction in the total daily recommended dose in of theKI free base reported in Table 3 while maintaining similarpharmacokinetics. For example, the currently approved daily dose fornilotinib hydrochloride is 600-800 mg based on the free base amount ofnilotinib. The oral administration of the nilotinib lauryl sulfate saltwill allow at least a 25% reduction in the daily dose, i.e. 450-600 mgwhile maintaining the same or substantially similar pharmacokineticssuch as C_(max), T_(max) and/or AUC. Alternatively, a patient receiving800 mg of nilotinib (as the hydrochloride) will be able to receive 600mg of nilotinib (as the lauryl sulfate) as maintain similar plasmalevels of nilotinib.

The solubility of many of the KI drugs is pH dependent. The solubilityof many of the KIs decrease with increasing pH. Patients taking a KIdrug may also be receiving or co-administered a gastric acid reducingagent such as an antacid, H₂ antagonist or proton pump inhibitor toreduce gastric acid secretion or increase gastric pH. Because thegastric acid reducing agent will increase the pH of a patient's stomach,the solubility of a co-administered KI drug will decrease in thepatient's stomach and thereby result in a decreased absorption. In orderto avoid this decreased absorption or gastric acid reducing agenteffect, patients are warned to take antacids at least two hours beforeor two hours after taking the KI drug or to discontinue the use of H₂antagonist or proton pump inhibitors during treatment with the KI drug.The present invention avoids the need for staggered administration ofantacids or discontinuing the use of H₂ antagonist or proton pumpinhibitors during treatment with the KI drug. The KI C₈-C₁₆ aliphaticsulfate salt of the present invention and specifically the KI laurylsulfate salts can be orally administered to a patient or healthy subjectand it will produce similar or substantially constant pharmacokineticvalues such as T_(max), C_(max) and AUC whether the administrationoccurs with or without a gastric reducing agent. A substantiallyconstant pharmacokinetic value means the measured pharmacokinetic valuesuch as C_(max) and/or AUC obtained after a single or multiple doseadministration of the composition or dosage form of the presentinvention, including but not limited to Embodiments A-G, to a patient orhealthy subject under fasting conditions with a gastric acid reducingagent does not change by more than 40%, 35%, 30%, 25%, 20%, 15%, 10%, or5% when the same composition is administered to the same patient orhealthy subject under fasting condition without a gastric acid reducingagent.

In certain embodiments of the present invention, a single oraladministration of the composition or dosage form prepared in accordancewith the present invention, including but not limited to EmbodimentsA-G, will produce a ratio of the KI C_(max) administered with a gastricacid reducing agent to the KI C_(max) administered without a gastricacid reducing agent(C_(max w/gastric acid reducing)/C_(max w/o gastric acid reducing)) ofabout 0.60 to about 2.5, preferably about 0.70 to about 2.0, morepreferably about 0.75 to about 1.5 and most preferably about 0.8 toabout 1.25. Similarly, in certain embodiments of the present invention,a single oral administration of the composition or dosage form preparedin accordance with the present invention, including but not limited toEmbodiments A-E will produce a ratio of the KI AUC_(0-∞) of thepharmaceutical composition administered with gastric acid reducing agentto the KI AUC_(0-∞) of the pharmaceutical composition administeredwithout gastric acid reducing agent(AUC_(0-∞ w/gastric acid reducing)/AUC_(0-∞ w/o gastric acid reducing))of about 0.60 to about 2.5, preferably about 0.70 to about 2.0, morepreferably about 0.75 to about 1.5, and most preferably about 0.80 toabout 1.25.

Certain embodiments of the present invention will employ the dosageforms of Embodiments A-G, the amounts of bosutinib, dasatinib,erlotinib, gefitinib, neratinib, nilotinib, and pazopanib recited inTable 1 to treat the conditions recited in Table 2 and theadministration will be orally with or without the co-administration of agastric acid reducing agent and the administration will producesubstantially constant pharmacokinetic values such as T_(max), C_(max)and AUC whether the administration occurs with or without a gastricreducing agents.

Certain embodiments of the present invention include methods fortreating cancer in human patients comprising the step of orallyadministering to the patient one or more dosage forms as described inEmbodiments A-G and co-administering a gastric acid reducing agent tothe patient wherein the dose of the KI C₈-C₁₆ aliphatic sulfate saltsand particularly the KI lauryl sulfate does not require an adjustment indose or a change in time of administration. Examples of the KIparticularly useful in this embodiment are bosutinib, dasatinib,erlotinib, gefitinib, neratinib, nilotinib, and pazopanib and in theamounts recited in Table 1 to treat the specific cancers recited inTable 2.

DESCRIPTION OF EMBODIMENTS

The following are provided by way of example only and are by no meansintended to be limiting.

Example 1

A nilotinib lauryl sulfate salt was prepared by dissolving 2.48 g ofnilotinib hydrochloride monohydrate in 1900 mL of 0.1N hydrochloric acidsolution and dissolving 1.16 g of sodium lauryl sulfate in 100 mL of0.1N hydrochloric acid solution. Once the nilotinib hydrochloridemonohydrate and sodium lauryl sulfate were dissolved, the two solutionswere mixed well and allowed to sit for 24 hours. The precipitatednilotinib lauryl sulfate was collected by removing the upper liquid anddried at 40° C. for 18 hours.

Example 2

Lauryl sulfate salts of acalabrutinib, afatinib, alectinib, axitinib,bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib,dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib,gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib,nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib,sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib may beformed in a similar manner as described in Example 1 by dissolving theacalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib,defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,imatinib, lapatinib, lenvatinib, neratinib, nintedanib, osimertinib,pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib,trametinib, vandetanib, or vemurafenib in a suitable solvent such as 0.1N HCl or a combination of 0.1 N HCl and a C₁-C₆ alcohol such asmethanol, ethanol, isopropanol and adding sodium lauryl sulfate or anaqueous solution of sodium lauryl sulfate to the acalabrutinib,afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib,ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib,enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib,lapatinib, lenvatinib, neratinib, nintedanib, osimertinib, pazopanib,ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib,vandetanib, or vemurafenib solution.

Example 3

A nilotinib lauryl sulfate capsule dosage form was prepared by mixingthe nilotinib lauryl sulfate (dry precipitate) prepared in Example 1with CAPMUL® MCM (glyceryl caprylate/caprate) and KOLLIPHOR® EL(polyoxyl 35 castor oil) and filling the liquid mixture into size 00hard gelatin capsules.

The composition of the capsule content is as follows:

mg wt % Nilotinib lauryl sulfate 75.0 12.5 (Dry precipitate) GlycerylCaprylate/Caprate 420.0 70.0 Polyoxyl 35 Castor Oil 105.0 17.5 Total600.0 100.0

Example 4

A nilotinib lauryl sulfate capsule was prepared by dissolving 1940 mg ofnilotinib lauryl sulfate (dry precipitate) and 1040 mg of poloxamer 188in 5 mL of ethanol. The solution was manually mixed with 3100 mg ofAVICEL PH 101 (microcrystalline cellulose) and 3100 mg of lactose. Theresulting granules were dried and milled through a 60 mesh screen andblended with 210 mg of colloidal silicon dioxide, 1040 mg of sodiumstarch glycolate and 100 mg of magnesium stearate. The dry solid blendwas filled into size 00 hard gelatin capsules.

The composition of the capsule content is as follows:

mg wt % Nilotinib lauryl sulfate 75.0 18.5 (Dry precipitate)Microcrystalline cellulose 119.5 29.4 Lactose 119.5 29.4 Sodium starchglycolate 40.0 9.9 Poloxamer 188 40.0 9.9 Colloidal Silicon Dioxide 8.02.0 Magnesium Stearate 4.0 0.9 Total 600.0 100.0

Example 5

The capsules similar to those prepared in Examples 3 and 4 but adjustedto contain a weight providing approximately 50 mg nilotinib free basewere administered to six (6) healthy adult beagle dogs in a fasted statealong with a capsule, obtained by dividing commercially available 200 mgTASIGNA capsule into 4 capsules (each contained equivalent to 50 mg ofnilotinib free base) in a single-center, single-dose study. Bloodsamples were drawn before dosing and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8,10, 12 and 24 hours after dosing. The mean nilotinib plasma values weredetermined as follows:

Capsule Prepared Capsule Prepared According to the According to theProcedure of Procedure of REFERENCE Example 3 Example 4 (TASIGNA)AUC₀₋₂₄ 4903.17 1906.55 1455.60 (ng · hr/mL) C_(max) 1114.65 436.93241.36 (ng/mL)

A graph of the mean plasma profiles is shown in FIG. 1.

The individual data from the study is shown in the following tables:

C_(max) 101 102 201 202 301 302 Mean SD CV (%) Ref 182.49 219.79 896.7072.73 12.88 63.59 241.36 330.35 136.9 Ex 3 577.78 1734.45 1006.851426.88 689.57 1252.34 1114.65 442.98 39.7 Ex 4 60.40 170.49 153.031499.36 62.88 675.44 436.93 569.02 130.2

AUC₀₋₂₄ 101 102 201 202 301 302 Mean SD CV (%) Ref 1458.11 651.135732.02 567.55 41.97 282.85 1455.60 2149.29 147.7 Ex 3 2522.04 5749.497045.54 5218.75 2082.71 6800.50 4903.17 2127.45 43.4 Ex 4 448.88 509.931759.07 5221.25 156.63 3343.55 1906.55 2010.55 105.5

Reference (TASIGNA) Time Blood concentration (ng/mL) (hr) 101 102 201202 301 302 Mean SD CV % 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00.25 0.00 0.00 0.00 0.00 1.01 0.00 0.17 0.41 241.2 0.5 34.67 0.00 0.006.03 5.16 4.00 8.31 13.16 158.4 1 103.75 84.24 6.54 17.65 12.88 58.2647.22 40.98 86.8 2 78.83 219.79 269.62 22.47 10.41 63.59 110.79 107.9297.4 3 40.06 133.04 673.00 15.14 6.33 50.31 152.98 258.70 169.1 4 30.2088.34 896.70 11.70 4.33 38.29 178.26 353.20 198.1 5 14.99 46.22 620.466.03 2.16 22.79 118.78 246.27 207.3 6 8.93 31.69 436.35 4.17 1.72 17.2983.36 173.27 207.9 8 87.93 15.50 295.18 2.16 1.48 9.67 68.65 115.69168.5 10 182.49 8.98 221.15 72.73 1.35 6.33 82.17 97.07 118.1 12 90.384.06 150.29 34.02 BLQ 4.74 56.69 63.01 111.1 24 2.72 BLQ 88.02 17.09 BLQBLQ 35.94 45.67 127.1

Capsule Prepared as in Example 3 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.0 0.25 28.66 0.00 0.00 0.00 0.00 0.00 4.78 11.70 244.8 0.5532.48 273.32 71.53 182.95 0.00 0.00 176.71 204.68 115.8 1 577.781734.45 494.18 1111.85 10.24 127.50 676.00 647.62 95.8 2 459.11 1520.121006.85 1426.88 301.22 1252.34 994.42 509.34 51.2 3 249.47 828.221002.63 883.51 689.57 1223.97 812.89 329.50 40.5 4 190.52 646.31 948.47694.87 404.08 1006.20 648.41 312.91 48.3 5 87.12 385.13 557.23 351.32187.37 556.34 354.08 190.90 53.9 6 53.79 237.90 490.02 223.13 112.63431.30 258.13 172.23 66.7 8 39.18 124.66 306.40 99.45 47.00 305.85153.76 122.27 79.5 10 107.48 66.81 220.19 56.47 31.28 211.28 115.5981.42 70.4 12 72.47 30.57 132.09 25.92 21.96 131.31 69.05 51.81 75.0 242.39 2.10 70.01 21.95 2.26 10.94 18.28 26.51 145.0

Capsule Prepared as in Example 4 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.0 0.25 3.21 0.00 0.00 1.07 3.05 0.00 1.22 1.54 126.2 0.556.72 5.90 9.64 149.41 44.04 0.00 44.28 56.29 127.1 1 40.54 170.49128.86 1059.13 62.88 12.24 245.69 402.74 163.9 2 22.22 108.08 81.271499.36 35.63 649.87 399.40 588.78 147.4 3 15.89 76.17 70.87 865.2019.63 675.44 287.20 379.83 132.3 4 10.36 55.68 54.68 653.73 12.47 500.68214.60 285.68 133.1 5 9.20 35.52 30.11 324.49 8.00 291.36 116.45 149.09128.0 6 26.37 30.08 23.71 224.68 4.25 254.89 94.00 113.68 120.9 8 60.4017.10 16.95 111.14 2.71 144.55 58.81 57.85 98.4 10 31.54 9.77 12.8065.06 1.78 90.92 35.31 35.43 100.3 12 14.50 5.54 153.03 39.79 1.11 48.3243.72 56.77 129.8 24 2.30 BLQ 42.60 9.98 BLQ 4.25 14.78 18.83 127.4

Example 6

Capsule dosage forms may be prepared using the lauryl sulfate salts ofacalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib,defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib,osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib,sunitinib, trametinib, vandetanib, or vemurafenib as prepared inExamples 1 and 2 using the procedure described in Example 3.

The composition of the capsule content is as follows:

Wt % KI lauryl sulfate  1-50 Carrier (preferably a wetting agent, 30-85emulsifying agent, solubilizing agent, surfactant or combinationthereof) with HLB value of less than 10 Carrier (preferably a wettingagent, 10-50 emulsifying agent, solubilizing agent, surfactant orcombination thereof) with HLB value of 10 or greater Total 100.0

Example 7

Capsule dosage forms may be prepared using the lauryl sulfate salts ofacalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib,defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib,osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib,sunitinib, trametinib, vandetanib, or vemurafenib as prepared inExamples 1 and 2 using the procedure described in Example 4.

The composition of the capsule content is as follows:

Wt % KI lauryl sulfate 1-50 Filler 10-80  disintegrant 0-25 Carrier(preferably a wetting agent, 2-40 emulsifying agent, solubilizing agent,surfactant or combination thereof) with HLB value of 10 or greaterGlidant/lubricant 0-10 Total 100.0

Example 8

Capsule dosage forms may be prepared using the lauryl sulfate salts ofacalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib,cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib,defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib,imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib,osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib,sunitinib, trametinib, vandetanib, or vemurafenib as prepared inExamples 1 and 2 using the procedure described in Example 3.

The composition of the capsule content is as follows:

Wt % KI lauryl sulfate 1-50 Carrier (liquid or solid) 10-95  Stabilizer0-50 Total 100.0

Example 9

A nilotinib lauryl sulfate salt was prepared by dissolving 2.92 g ofnilotinib hydrochloride monohydrate in 2900 mL of 0.1N hydrochloric acidsolution and dissolving 1.50 g of sodium lauryl sulfate in 100 mL of0.1N hydrochloric acid solution. Once the nilotinib hydrochloridemonohydrate and sodium lauryl sulfate were dissolved, the two solutionswere combined, mixed well and allowed to sit for 24 hours. Theprecipitated nilotinib lauryl sulfate was collected by removing theupper liquid and the collected precipitate was dried at 40° C. for 18hours.

A nilotinib lauryl sulfate capsule dosage form was prepared by mixingthe nilotinib lauryl sulfate (dry precipitate) with CAPMUL® MCM(glyceryl caprylate/caprate) and KOLLIPHOR® EL (polyoxyl 35 castor oil)and filling the liquid mixture into size 00 hard gelatin capsules.

The composition of the capsule content is as follows:

mg wt % Nilotinib lauryl sulfate 100.0 16.0 (Dry precipitate) GlycerylCaprylate/Caprate 420.0 67.2 Polyoxyl 35 Castor Oil 105.0 16.8 Total625.0 100.0

Example 10

Capsules prepared according to Example 9 were administered to nine (9)healthy subjects under fasted and fed conditions. The administration wasa randomized, open-label, single dose, three treatment, three sequences,three periods, and crossover design with at least a 5-day washout periodbetween doses. The Reference drug (Ref) was TASIGNA Capsule, (comprisingnilotinib monohydrate monohydrochloride, colloidal silicon dioxide,crospovidone, lactose monohydrate, magnesium stearate and poloxamer188), with a strength of 200 mg (free base) while the Test drug (Test)was a capsule prepared according to the procedure of Example 9 butcontaining approximately 50 mg free base of nilotinib. Based on theresults reported in Example 5 herein, the dose of the Test capsulesselected was 100 mg (2 capsules, each capsule containing 50 mg nilotinibfree base). The nine (9) healthy subjects enrolled in this study wererandomized to one of the sequences as shown in the following table.

Period I Period II Period III Sequence 1 Ref (fasted) Test (fasted) Test(fed) Sequence 2 Test (fasted) Test (fed) Ref (fasted) Sequence 3 Test(fed) Ref (fasted) Test (fasted)

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 36 and 48hours after dosing. AUC₀₋₄₈, AUC_(0-∞), C_(max), T_(max), and T_(1/2)were determined for each subject based on non-compartmental analyses.The results of the study were normalized to 200 mg dose and summarizedin Table 1. Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) wereanalyzed by ANOVA. The sequence, subject (sequence), period andtreatment effects were included in the model. A comparison of the dataobtained from the Test and Ref dosing is shown in Table 2. The datashows that the compositions of the present invention exhibit an increaseof C_(max) by 3.4 fold and an increase of AUC by 2.3 fold compared tothe U.S. FDA approved nilotinib HCl. The data also shows that thecompositions of the present invention do not exhibit a food effect i.e.,the compositions of the present invention exhibit comparablepharmacokinetics under fasted and fed conditions.

TABLE 1 The Pharmacokinetic Parameters for Reference and TestFormulations (Normalized to 200 mg dose) Normalized to 200 mg doseTreatment Parameters Mean Ref_(Fasted) C_(max) (ng/mL) 588 AUC₀₋₄₈ (ng ·h/mL) 11271 AUC_(0-∞) (ng · h/mL) 12697 Test_(Fasted) C_(max) (ng/mL)2022 AUC₀₋₄₈ (ng · h/mL) 26766 AUC_(0-∞) (ng · h/mL) 28390 Test_(Fed)C_(max) (ng/mL) 1864 AUC₀₋₄₈ (ng · h/mL) 27980 AUC_(0-∞) (ng · h/mL)29378 Ref_(Fasted): Tasigna Capsule 200 mg (free base) under fastedcondition Test_(Fasted): Test drug (Test) 100 mg (free base) (2capsules, 50 mg* 2) under fasted condition Test_(Fed): Test drug (Test)100 mg (free base) (2 capsules, 50 mg* 2) under fed condition

TABLE 2 The Comparisons between Test vs. Reference and Test_(Fed) vs.Test_(Fasted) (Normalized to 200 mg dose) Geometric 90% ConfidenceComparisons Parameters Mean Ratios Intervals Test~Ref C_(max) 341.53%289.35%~403.12% (Fasted) (ng/mL) AUC₀₋₄₈ 235.14% 202.31%~273.29% (ng ·h/mL) AUC_(0-∞) 224.28% 197.49%~254.69% (ng · h/mL)Test_(Fed)~Test_(Fasted) C_(max) 93.48%  87.04%~100.41% (ng/mL) AUC₀₋₄₈107.24%  94.52%~121.68% (ng · h/mL) AUC_(0-∞) 105.73%  93.83%~119.14%(ng · h/mL)

The individual subject data normalized to 200 mg dose obtained from thestudy is as follows:

Reference Drug (TASIGNA ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 0 0 0 0 0 0 0 0 0 0 0.5 10730.8 51.6 87.9 88 105 98.7 58.2 138 1 385 139 283 296 252 251 351 262289 2 562 277 508 541 389 367 536 569 362 3 460 439 586 711 440 459 643787 447 4 497 438 612 824 514 467 631 755 431 5 383 359 518 756 434 350463 633 372 6 347 348 461 708 402 321 437 572 329 7 349 330 397 597 413311 444 531 317 8 300 311 430 594 360 290 393 504 301 10 266 308 377 547343 294 501 467 289 12 269 255 381 480 318 237 334 390 288 14 254 232352 473 293 225 347 398 238 24 169 176 284 386 204 156 335 365 120 3660.6 74.7 157 157 24.1 153 225 96.1 21.3 48 16.5 19.2 72.6 47.6 N.D. 121156 27 N.D.

Test Drug under fasted condition (Concentration (ng/mL)) Time Subject(hr) 1 2 3 4 5 6 7 8 9 0 0 0 0 0 0 0 0 0 0 0.5 141.8 145.6 150 1038 338620 772 316 390 1 592 430 444 1932 1068 1110 2320 616 1590 2 2120 944720 2360 1534 2080 3300 1832 1856 3 2060 1164 1452 2160 1464 2180 30001588 1624 4 1822 1438 1582 2020 1354 1998 2440 1480 1462 5 1326 842 13541662 1112 1204 1468 1150 1178 6 1134 742 1090 1526 984 922 1250 1016 9367 1054 708 1046 1536 916 896 1164 976 904 8 954 612 962 1370 822 7821006 890 848 10 966 556 876 1302 848 606 1316 812 808 12 736 428 7621244 772 744 918 750 722 14 688 370 692 1046 730 636 824 712 726 24 576161.8 494 960 274 480 686 538 408 36 230 21.6 230 400 N.D. 184.8 288135.2 72.8 48 80.8 N.D. 107.6 185.6 N.D. 108.4 166 34 N.D.

Test Drug under fed condition (Concentration (ng/mL)) Time Subject (hr)1 2 3 4 5 6 7 8 9 0 0 0 0 0 0 0 0 0 0 0.5 127.4 24.6 0 0 146 0 0 0 0 1932 220 131.4 68 766 47.6 159 408 0 2 1742 832 394 962 1332 374 10181312 438 3 1836 1620 1302 1938 1710 1020 2060 1734 1646 4 1796 1472 14702440 1694 1654 2580 1720 1726 5 1418 1102 1318 2120 1642 1528 1534 16021290 6 1212 1032 1202 1808 1376 1210 1382 1408 1198 7 974 894 1002 16021308 1014 1218 1242 1068 8 928 802 972 1356 1118 854 1084 1124 1006 10926 748 876 1222 1034 742 1136 1086 876 12 778 672 812 1200 910 694 1002904 766 14 752 506 700 1056 812 628 890 866 776 24 636 260 526 802 750462 788 704 436 36 177.8 47 208 382 78.4 204 416 290 119.8 48 46.8 N.D.77.6 133.4 N.D. 92 262 69.2 21.8

A graph of the normalized mean plasma profiles is shown in FIG. 2.

Example 11

A dasatinib lauryl sulfate salt was prepared by dissolving 253.0 mg ofdasatinib monohydrate in 1000 mL of 0.1N hydrochloric acid solution anddissolving 432.0 mg of sodium lauryl sulfate in 100 mL of 0.1Nhydrochloric acid solution. Once the dasatinib monohydrate and sodiumlauryl sulfate were dissolved, the two solutions were combined, mixedwell and allowed to sit for 20 hours. The precipitated dasatinib laurylsulfate was collected by removing the upper liquid and the collectedprecipitate was dried at 50° C. for 20 hours.

The precipitate was analyzed by dissolving approximately 10.44 mg of theprecipitate in 50 mL of methanol followed by 5 minutes of sonication and5 minutes of stirring and subjecting the solution to high pressureliquid chromatography (HPLC). The results of the analysis indicated thatthe precipitate contained dasatinib dilauryl sulfate.

Example 12

A dasatinib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   -   a. 13 g of dasatinib monohydrate (dasatinib.H₂O) and 650 mL of        methanol (50V) were combined and stirred at 50-55° C.;    -   b. 7.4 g of sodium lauryl sulfate (SLS) (1 molar equivalent to        the dasatinib.H₂O) was combined with 39 mL of methanol (3V) and        25.7 mL of 1 N HCl (1 molar equivalent to the SLS);    -   c. The composition of step (b) was added to the composition of        step (a) and stirred for 30 minutes while maintaining the        temperature at 50-55° C., then cooled to room temperature for        about an hour;    -   d. 650 mL of purified water (50V) was added to the reaction mass        of step (c) and stirred at room temperature for 30 minutes.    -   e. The solvent was removed from the reaction mass of step (d)        and the residue collected;    -   f. 260 mL of ethyl acetate (20V) was added to the residue of        step (e) and the resulting reaction mass was washed with 130 mL        of purified water for three times (10V×3);    -   g. The organic extracts were combined and 130 mL of methanol        (10V) was added;    -   h. The reaction mass of step (g) was dried in a vacuum at 40° C.        for 6 hours to obtain crude dasatinib monolauryl sulfate        (dasatinib-1LS);    -   i. The crude dasatinib-1LS was combined with 130 mL of hexane        (10 V) and stirred for 30 minutes, the solids were isolated by        filtration, washed with hexane and dried in a vacuum at 40° C.        for 16 hours to obtain dasatinib-1LS as a white powder which was        exhibited a chromatographic purity greater than 99%.

The X-ray Powder Diffraction Pattern (“XRPD”) for the white powderdasatinib monolauryl sulfate salt is shown in FIG. 3. The XRPD wasobtained using D8 Discover with GADDS (Bruker AXS Gmbh, Karlsruhe,Germany) (GADDS: General Area Diffraction Detection System) andemploying the following testing condition:

-   -   Cukα₁₊₂=1.54184 Å,    -   40 kV 40 mA    -   Beam size: 1.0 mm (the collimator system allows the analysis of        1000 μm² surface areas)    -   Detector type: Vantec-2000 (14×14 cm² area and 2048×2048 pixel        density) Sample to detector distance: 15.05 cm    -   300 sec/frame (The exposure time was 300 s per frame).

The above synthesis was conducted multiple times and the results aresummarized in the following table:

dasatinib•H₂O SLS (eq) dasatinib-1LS Yield Purity 13 g 1 16.17 g 83.00%99.96% 30 g 1 42.0 g 93.90% 99.91% 75 g 1 104.78 g 93.70%  100% 75 g 1106.68 g 95.40%  100%

Example 13

A dasatinib dilauryl sulfate salt was prepared by the following generalprocedure:

-   -   a. 10 g of dasatinib.H₂O and 500 mL of methanol (50V) were        combined and stirred at 50-55° C.;    -   b. 11.4 g of SLS (2 molar equivalent to the dasatinib.H₂O) was        combined with 30 mL of methanol (3V) and 79 mL of 1 N HCl (2        molar equivalent to the SLS);    -   c. The composition of step (b) was added to the composition of        step (a) and stirred for 30 minutes while maintaining the        temperature at 50-55° C., then cooled to room temperature for        about an hour;    -   d. 500 mL of Purified water (50V) was added to the reaction mass        of step (c) and stirred at room temperature for 30 minutes.    -   e. The solvent was removed from the reaction mass of step (d)        and the residue collected;    -   f. 200 mL of ethyl acetate (20V) was added to the residue of        step (e) and the resulting reaction mass was washed with 100 mL        of purified water for three times (10V×3);    -   g. The organic extracts were combined and 100 mL of methanol        (10V) was added;    -   h. The reaction mass of step (g) was dried in a vacuum at 40° C.        for 6 hours to obtain crude dasatinib dilauryl sulfate        (dasatinib-2LS);    -   i. The crude dasatinib-2LS was combined with 100 mL of hexane        (10 V) and stirred for 30 minutes, the solids were isolated by        filtration, washed with hexane and dried in a vacuum at 40° C.        for 16 hours to obtain dasatinib dilauryl sulfate as a white        powder which was exhibited a chromatographic purity greater than        99%.

The XRPD for the white powder dasatinib dilauryl sulfate salt is shownin FIG. 4. The XRPD was obtained using D8 Discover with GADDS (BrukerAXS Gmbh, Karlsruhe, Germany) (GADDS: General Area Diffraction DetectionSystem) and employing the following testing condition:

-   -   Cukα₁₊₂=1.54184 Å,    -   40 kV 40 mA    -   Beam size: 1.0 mm (the collimator system allows the analysis of        1000 μm² surface areas)    -   Detector type: Vantec-2000 (14×14 cm² area and 2048×2048 pixel        density) Sample to detector distance: 15.05 cm    -   300 sec/frame (The exposure time was 300 s per frame).

The above synthesis was conducted multiple times and the results aresummarized in the following table:

dasatinib•H₂O SLS (eq) dasatinib-2LS Yield Purity 10 g 2 18.38 g  91.10%99.97% 53 g 2 90.3 g 84.50%  100% 33 g 2 56.6 g 85.00% 99.97% 38 g 265.2 g 85.00% 99.98%

Example 14

A dasatinib lauryl sulfate salt was prepared by dissolving 1.012 g ofdasatinib monohydrate in 1800 mL of 0.1N hydrochloric acid (HCl)solution and dissolving 1.728 g of sodium lauryl sulfate in 200 mL of0.1N hydrochloric acid (HCl) solution. Once the dasatinib monohydrateand sodium lauryl sulfate were dissolved, the two solutions were mixedwell, dilute with 0.1N HCl to total volume of 5330 mL and stir for 2hours. The precipitated dasatinib lauryl sulfate was collected byremoving the upper liquid and dried at 50° C. for 20 hours.

Example 15

A dasatinib lauryl sulfate capsule dosage form was prepared by mixing522.0 mg of the dasatinib lauryl sulfate (dry precipitate) prepared inExample 14 with 2100.0 mg of CAPMUL® MCM (glyceryl caprylate/caprate)and 525.0 mg of KOLLIPHOR® EL (polyoxyl 35 castor oil) and filling thesuspension mixture into size 00 hard gelatin capsules.

The composition of the capsule content is as follows:

mg/cap wt % Dasatinib lauryl sulfate (Dry precipitate) 104.4 16.6Glyceryl Caprylate/Caprate 420.0 66.7 Polyoxyl 35 Castor Oil 105.0 16.7Total 629.4 100.0

Example 16

A pazopanib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   -   a. 20 g of pazopanib hydrochloride (PZB.HCl), 200 mL methanol        (10V) and 400 mL purified water (20V) were combined and stirred        at 50-55° C.;    -   b. 12.17 g sodium lauryl sulfate (SLS) (1 molar equivalent to        the PZB.HCl) was combined with 60 mL of methanol (3V) and 60 mL        of purified water (3V);    -   c. The composition of step (b) was added to the composition of        step (a) and stirred for 30 minutes while maintaining the        temperature at 50-55° C., then cooled to room temperature for        about an hour;    -   d. 400 mL of purified water (20V) was added to the cooled        reaction mass of step (c) and stirred at room temperature for 1        hour;    -   e. The precipitate (white crystals) of step (d) was collected by        filtration, washed with 100 mL of purified water (5V) to obtain        crude pazopanib monolauryl sulfate (PZB-1LS);    -   f. The crude PZB-1LS was combined with 200 mL of purified water        (10 V) stirred for 30 minutes, the solids were collected by        filtration, washed with 100 mL of purified water (5 V) and        vacuum dried to obtain 28 g of PZB-1LS as a white powder which        was exhibited a chromatographic purity 100% and a yield of 94%.

The solubility of the pazopanib monolauryl sulfate prepared above and acommercially available sample of pazopanib hydrochloride was measured byadding the sample to 300 mL of the designated medium at 37° C. andshaking or stirring for at least 18 hours to obtain a saturatedcondition. The reaction mass was filtered and the filtrate solution wasmeasured by HPLC.

Pazopanib Pazopanib Monolauryl Hydrochloride Sulfate pH condition(μg/mL) (μg/mL) 0.1N HCl, pH = 1.0 3361.05 118.68 0.05M acetate buffer,1.1924 0.3212 pH = 4.5 0.05M phosphate buffer, 0.0 1.242 pH = 6.8

Example 17

A PZB-1LS salt was prepared by the procedure of Example 16 wherein 17.4g of PZB.HCl and 10.58 g of SLS were used as the starting materials. Theprocess resulted in 20.5 g of PZB-1LS (80% yield) with a chromatographicpurity of 99.99%.

Example 18

A pazopanib lauryl sulfate capsule dosage form was prepared by mixing1009.7 mg of the PZB-1LS prepared according to the procedure of Examples16 & 17, 4981.0 mg of CAPMUL® 808G (glyceryl monocaprylate), 1.25 mg ofbutylated hydroxytoluene, 281.8 mg of PURAC® FCC 88 (lactic acid), and960.1 mg of KOLLIPHOR® ELP (polyoxyl 35 castor oil) and filling theliquid mixture into size 0 hard gelatin capsules.

The composition of the capsule content is as follows:

mg wt % Pazopanib mono lauryl sulfate 80.5 13.94 (EQ to 50 mg base)Glyceryl monocaprylate 400.0 69.25 Polyoxyl 35 Castor Oil 75.0 12.98Lactic acid 22 3.81 Butylated hydroxytoluene 0.1 0.02 Total 577.6 100.00

The above pazopanib monolauryl sulfate capsule was tested using thefollowing High Performance Liquid Chromatography (HPLC) method:

Parameter Setting/Description System HPLC Equipped with a UV/VisDetector Column Develosil RP Aqueous-3, C-30 (3 μm, 150*4.6 mm)Detection UV at 268 nm Flow rate 1 mL/min Injection volume 10 μL Columntemperature 35° C. Sample temperature Ambient Run time 40 minutes Modeof Analysis Gradient as shown below: Time (min) Mobile phase A Mobilephase B 0 90 10 1 90 10 31 46 54 33 90 10 40 90 10

The mobile phase A was water/trifluoracetic acid in a volume ratio of100/0.1.

The mobile phase B was acetonitrile/trifluoracetic acid in a volumeratio of 100/0.1.

The test sample was prepared by weighing approximately 8.0 mg ofpazopanib monolauryl sulfate into a 25 mL amber volumetric flask, addingabout 20 mL of a diluent comprising acetonitrile/water/trifluoraceticacid in a volume ratio of 50/50/0.1, sonicating for about 5 minutes andstirring at about 800 rpms for about 5 minutes until the pazopanibmonolauryl sulfate is dissolved. Additional diluent is added so the testsample is approximately 0.20 mg of pazopanib per mL.

The results of the HPLC testing was as follows:

RRT 0.31 0.60 0.85 0.95 0.98 1.17 1.30 Room Temp. 0.01 60° C./75% 0.010.09 0.02 0.06 0.01 0.01 R.H. (1 week) RRT = relative retention time.

The capsules were stored in a high-density polyethylene (HDPE) bottlewith child resistant closure and foil induction seal (126 c.c, with 2˜3g of silica gel).

The above table demonstrates the capsules have not more than (“NMT”)0.5% of any individual impurity, preferably NMT 0.35% of any individualimpurity and most preferably NMT 0.25% of any individual impurity andthe total impurity should be NMT 1.0%, preferably NMT 0.75% and mostpreferably NMT 0.60%.

The pazopanib monolauryl sulfate capsule release not less than 90%,preferably not less than 85% and most preferably not less than 80% ofthe pazopanib within 45 minutes of in vitro testing using a USP Type IIApparatus (Paddle) with 500 ml of 0.1 N HCl at 75 rpm, with or without asinker and 37° C.

Example 19

A pazopanib lauryl sulfate capsule was prepared by dissolving 226 mg ofpoloxamer 188 in 1.2 g of ethanol. The solution was manually mixed with2421 mg of PZB-1LS prepared according to the procedure of Examples 16and 17, 1398.3 mg of lactose monohydrate and 238.9 mg of polyvinylpyrrolidone. The resulting granules were dried and milled through a 60mesh screen and blended with 28.1 mg of colloidal silicon dioxide, 216.2mg of sodium starch glycolate, 1259.1 mg of lactose monohydrate and 29.2mg of magnesium stearate. The dry solid blend was filled into size 0hard gelatin capsules.

The composition of the capsule content is as follows:

mg wt % Granule Pazopanib mono lauryl sulfate 80.5 40.25 (EQ to 50 mgbase) Lactose monohydrate 46.7 23.35 Polyvinyl pyrrolidone 8.0 4.00Poloxamer 188 8.2 4.10 Ethanol 40.0 — External phase Lactose monohydrate46.6 23.30 Sodium starch glycolate 8.0 4.00 Colloidal Silicon Dioxide1.0 0.50 Magnesium Stearate 1.0 0.50 Total 200.0 100.00

The above pazopanib monolauryl sulfate capsule was tested using the HPLCmethod described in Example 18 and the following results were obtained:

RRT 0.31 0.60 0.85 0.95 0.98 1.17 1.30 Room Temp. 0.01 0.02 0.02 60°C./75% 0.01 0.04 0.02 R.H. (1 week)

The capsules were stored in a high-density polyethylene (HDPE) bottlewith child resistant closure and foil induction seal (126 c.c, with 2˜3g of silica gel).

The above table demonstrates the capsules have NMT 0.5% of anyindividual impurity, preferably NMT 0.35% of any individual impurity andmost preferably NMT 0.25% of any individual impurity and the totalimpurity should be NMT 1.0%, preferably NMT 0.75% and most preferablyNMT 0.60%.

The pazopanib monolauryl sulfate capsule should release not less than90%, preferably not less than 85% and most preferably not less than 80%of the pazopanib within 45 minutes of in vitro testing using a USP TypeII Apparatus (Paddle) with 500 ml of 0.1 N HCl at 75 rpm, with orwithout a sinker and 37° C.

Example 20

The capsules prepared in Examples 18 and 19 containing PZB-1LSequivalent to 50 mg of pazopanib free base were administered to six (6)healthy adult beagle dogs in a fasted state along with a capsule,obtained by dividing the content from a commercially available 200 mgVOTRIENT FILM COATED tablet (containing 216.7 mg of pazopanib HCl) into4 capsules (each capsule containing pazopanib hydrochloride equivalentto 50 mg of pazopanib free base) in a single-center, single-dose study.Blood samples were drawn before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12 and 24 hours after dosing. The mean pazopanib plasma valueswere determined as follows:

Capsule Prepared Capsule Prepared According to the According to theREFERENCE Procedure of Procedure of (VOTRIENT) Example 18 (T1) Example19 (T2) (R) AUC₀₋₂₄ 7885.29 2394.47 1279.27 (ng · hr/mL) C_(max) 2608.42847.44 313.00 (ng/mL)

A graph of the mean plasma profiles is shown in FIG. 5.

The individual data from the study is shown in the following tables:

C_(max) (ng/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 138.77 112.0471.65 215.42 989.72 350.40 313.00 345.79 110.5 Ex 18 1264.89 1475.946776.81 1599.92 679.50 3853.45 2608.42 2313.05 88.7 Ex 19 229.52 288.57780.60 3396.11 82.23 307.60 847.44 1270.54 149.9

AUC₀₋₂₄ (ng · hr/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 368.96268.45 816.48 693.44 3834.53 1693.74 1279.27 1349.74 105.5 Ex 18 6429.595400.80 16849.29 6819.58 1525.84 10286.63 7885.29 5215.17 66.1 Ex 19539.82 663.49 3989.39 7765.88 356.31 1051.93 2394.47 2959.33 123.6

Reference (VOTRIENT) Time Blood concentration (ng/mL) (hr) 101 102 201202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA 0.5 BLQ 2.14BLQ BLQ 4.75 4.82 3.90 1.53 39.2 1 13.47 5.83 52.69 204.08 188.16 25.8781.68 90.20 110.4 1.5 11.99 9.72 49.62 215.42 586.82 314.89 198.08226.81 114.5 2 16.44 11.59 71.65 180.47 795.17 287.95 227.21 297.85131.1 2.5 42.82 112.04 57.08 170.43 955.39 350.40 281.36 348.50 123.9 3123.99 105.75 37.42 115.31 989.72 270.95 273.86 358.95 131.1 4 138.7768.96 18.93 97.81 797.13 170.26 215.31 289.89 134.6 6 10.90 6.69 2.5333.64 195.30 14.14 43.87 74.97 170.9 8 3.65 1.66 BLQ 7.76 57.16 15.4117.13 22.99 134.2 12 BLQ BLQ BLQ BLQ 7.24 70.36 38.80 44.64 115.1 24 BLQBLQ 68.80 BLQ 1.90 17.63 29.44 34.98 118.8

Capsule Prepared as in Example 18 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA0.5 762.79 1360.21 3739.87 1599.92 25.98 133.55 1270.39 1364.82 107.4 11083.37 1475.94 6776.81 1027.53 179.49 737.07 1880.04 2437.27 129.6 1.51208.80 1396.37 5642.07 830.73 679.50 3528.04 2214.25 1971.06 89.0 21091.19 1261.88 5102.56 556.34 424.78 3853.45 2048.37 1948.50 95.1 2.51241.99 1013.86 3091.67 459.99 333.63 2913.10 1509.04 1206.21 79.9 31146.82 928.57 2717.07 410.02 214.64 2067.39 1247.42 970.76 77.8 41264.89 539.23 1482.79 281.44 126.69 1290.15 830.86 584.31 70.3 6 280.32191.84 139.86 95.50 32.12 125.05 144.11 84.99 59.0 8 96.69 56.50 39.6316.01 10.29 29.62 41.46 31.74 76.6 12 13.19 9.82 6.10 1.71 31.30 6.1511.38 10.50 92.3 24 3.64 1.61 BLQ 599.99 1.27 138.35 148.97 258.93 173.8

Capsule Prepared as in Example 19 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA0.5 229.52 288.57 2.09 2.23 82.23 307.60 152.04 140.46 92.4 1 209.08191.32 39.73 14.02 61.28 176.33 115.29 86.24 74.8 1.5 159.86 170.91162.41 414.05 47.57 144.37 183.19 121.92 66.6 2 123.06 97.88 356.843396.11 43.84 130.32 691.34 1329.42 192.3 2.5 99.25 83.80 419.43 3062.0532.74 93.08 631.73 1198.68 189.7 3 76.97 56.02 727.55 2078.21 26.5177.51 507.13 814.98 160.7 4 42.10 39.99 780.60 1350.90 16.30 54.69380.76 560.54 147.2 6 3.70 5.36 385.73 192.92 2.47 5.34 99.25 159.36160.6 8 1.16 1.49 174.68 49.60 BLQ BLQ 56.73 81.86 144.3 12 BLQ BLQ39.21 5.75 BLQ 44.87 29.94 21.14 70.6 24 BLQ 15.14 28.90 26.00 17.0510.12 19.44 7.80 40.1

Example 21

A nintedanib dilauryl sulfate salt was prepared by the following generalprocedure:

-   -   a. 15 g of nintedanib esylate was added to a co-solvent of ethyl        acetate/10% aqueous NaHCO₃ (450 ml/150 ml) (30V/10V) and stirred        at 40° C. for 1 hour;    -   b. The organic layer of the reaction mixture of step (a) was        separated and washed twice with 150 mL of purified water        (10V×2);    -   c. The organic extracts of step (b) were combined and        concentrated to obtain nintedanib free base as a yellow powder        (12.3 g, 98.7% yield);    -   d. 738 mL of methanol (60V) was added to the 12.3 g of        nintedanib free base and the mixture was stirred at 50-55° C.;    -   e. An SLS solution was prepared by dissolving 13.1 g of SLS (2        molar equivalents to the nintedanib) in a co-solvent of 36.9 mL        methanol/90 mL 1 N HCl (3V);    -   f. The SLS solution of step (e) is added to the mixture of        step (d) and stirred at 50-55° C. for 30 minutes;    -   g. 246 mL of purified water (20V) was added to the reaction        mixture of step (f) and stirred at room temperature for 1 hour;    -   h. The precipitate (crystals) of step (g) were collected by        filtration, washed with 61.5 mL of purified water (5V) to obtain        crude nintedanib dilauryl sulfate;    -   i. The crude nintedanib dilauryl sulfate was combined with 123        mL of purified water (10 V), stirred for 30 minutes, the solids        were collected by filtration, washed with 61.5 mL of purified        water (5 V) and vacuum dried to obtain 21.83 g of nintedanib        dilauryl sulfate as a golden yellow powder which was exhibited a        chromatographic purity 100% and a yield of 89.3%.

Example 21A

A nintedanib dilauryl sulfate tablet dosage form was prepared by thefollowing wet granulating process:

-   -   (i) 9.940 g of nintedanib dilauryl sulfate prepared according to        the procedure of Example 21 was mixed with 1.800 g of poloxamer        407 and 1.575 g of poloxamer 188;    -   (ii) the mixture of step (i) is granulated with a solution        comprising 1.500 g of alcohol (95%) and 1.500 g of purified        water;    -   (iii) 6.000 g of anhydrous lactose and 8.278 g of        microcrystalline cellulose are passed through a 40 mesh sieve,        added to the granules of step (ii) and the resulting composition        is blended;    -   (iv) the blend of step (iii) is dried in an oven at 50° C. to        evaporate the alcohol and water and after drying is passed        through a 40 mesh sieve;    -   (v) the dried and sieved material from step (iv) is mixed with        0.600 g of colloidal silicon dioxide and 1.500 g of polyethylene        oxide with an average molecular weight of 7,000,000 (Polyox        WSR303) which have been passed through a 40 mesh sieve;    -   (vi) 0.007 g of butylated hydroxytoluene (BHT) is passed through        a 40 mesh sieve, added to the composition of step (v) and mixed;    -   (vii) 0.300 g of magnesium stearate is passed through a 40 mesh        sieve, added to the composition of step (vi) and blended to        obtain a final blend; and    -   (viii) the final blend is compressed into tablets using a        capsule-shaped punch (17.5 mm length and 7.1 mm width) and with        a target hardness of about 10 kp.

The composition of the tablet is as follows:

mg wt % Nintedanib dilauryl sulfate, NTB-2LS 198.80 33.13 (EQ to 100 mgstrength) Poloxamer 407 36.00 6.00 Poloxamer 188 31.50 5.25 Anhydrouslactose 120.00 20.00 Microcrystalline cellulose 165.56 27.59 Colloidalsilicon dioxide 12.00 2.00 Polyethylene oxide 7000000 (Polyox 30.00 5.00WSR303) Butylated Hydroxytoluene 0.14 0.02 Magnesium stearate 6.00 1.00Total 600.00 100.00 95% alcohol 30.0 N/A Purified water 30.0 N/A

Example 21B

A nintedanib dilauryl sulfate tablet dosage form was prepared by theprocedure described in Example 21A and the composition of the tablet isas follows:

mg wt % Nintedanib dilauryl sulfate, NTB-2LS 198.80 33.13 (EQ to 100 mgstrength) Poloxamer 407 36.00 6.00 Poloxamer 188 31.50 5.25 Anhydrouslactose 120.00 20.00 Microcrystalline cellulose 123.56 20.59 Colloidalsilicon dioxide 12.00 2.00 Polyethylene oxide 7000000 (Polyox 72.0012.00 WSR303) Butylated Hydroxytoluene 0.14 0.02 Magnesium stearate 6.001.00 Total 600.00 100.00 95% alcohol 30.0 N/A Purified water 30.0 N/A

Example 21C

The dosage forms prepared in Examples 21A and 21B (n=2) were testedusing a USP Type II Apparatus (Paddle) with 675 ml of 0.1 N HCl for 2hours followed by a pH change to 6.8 (final volume: 900 ml) with 0.1%sodium lauryl sulfite at 100 rpm, with a sinker and 37° C. The resultsof this dissolution testing are as follows:

Time (Hour) 0.5 1 1.5 2 4 6 8 10 12 14 16 18 Ex 21A 1.8 3.5 4.6 5.3 63.496.5 101 100.8 101.0 100.9 100.9 101.0 Ex 21B 0.4 0.8 1.3 1.8 24.1 4666.1 84.8 102.3 103.7 103.8 104.0

The dosage forms prepared in Examples 21A and 21B (n=2) were also testedusing a USP Type II Apparatus (Paddle) with 900 ml of an aqueous mediawith a pH of 6.8 and 0.1% sodium lauryl sulfite at 100 rpm, with asinker and 37° C. The results of this dissolution testing are asfollows:

Time (Hour) 0.5 1 1.5 2 4 6 8 10 12 14 16 Ex 21A 6.8 12.9 19.9 27.6 63.698.4 98.7 98.8 98.9 98.8 98.9 Ex 21B 1.0 1.9 3.2 4.9 15.7 29.5 45.2 62.378.4 90.7 99.0

The above in vitro dissolution data demonstrates that dosage formsprepared in accordance with the present invention can exhibit sustainedrelease properties allowing for once or twice daily dosing. For example,a sustained release dosage form will release nintedanib lauryl sulfatesalts when tested using a USP Type II Apparatus (Paddle) with 900 ml ofan aqueous media with a pH of 6.8 and 0.1% sodium lauryl sulfite at 75rpm as follows:

Time (hour) Preferred More Preferred Most Preferred 2   0-40% 0-35% 0-304   5-70% 7.5%-60%       10-50% 6  10-100% 15-100%  20-100% 10 NLT 45%NLT 50% NLT55% 12 NLT 50% NLT 60% NLT 70%  NLT: not less than

The dosage forms prepared in Examples 21A and 21B were also tested forimpurities using the following HPLC methods:

Parameter Setting/Description System HPLC Equipped with a UV/VisDetector Column Nucleodur C18 Gravity, 50 mm*4 mm, 5 μm Detection 0~7min: UV at 235 nm; 7~19 min: UV at 357 nm Flow rate 1.0 mL/min Injectionvolume 5 μL Column temperature 40° C. Sample temperature Ambient Runtime 19 minutes Mode of Analysis Gradient as shown below: Time (min)Mobile phase A Mobile phase B 0 5 95 13 70 30 14 70 30 15 5 95 19 5 95

Mobile phase A was 100% acetonitrile.

Mobile phase B was 0.0075M diammonium hydrogen phosphate (pH 6.4±0.2).

The test samples were prepared in triplicate by crushing the tablet andtransferring the crushed material into a 100 mL amber volumetric flask,adding about 80 mL of methanol, stirring for about 120 minutes or longeruntil the material disintegrates, sonicating for an additional 15minutes and stirring at about 800 rpms for about 10 minutes. Theresulting composition is filtered through a 0.45 μm nylon filter withthe first 3 mL of filtrate discarded.

The nintedanib dilauryl sulfate tablets prepared in Examples 21A and 21Bwere determined to have the following impurity profile:

0.23 0.59 0.92 1.10 1.34 1.38 1.41 1.44 RRT % Impurity Ex 21A Initial0.01 0.01 0.04 0.03 60° C./75% 0.01 0.01 0.08 0.03 R.H. 2 weeks Ex21BInitial 0.01 0.05 0.03 60° C./75% 0.01 0.06 0.03 R.H. 2 weeks

The above data demonstrate the nintedanib lauryl sulfate dosage forms ofthe present invention have NMT 0.5% of any individual impurity,preferably NMT 0.35% of any individual impurity and most preferably NMT0.25% of any individual impurity and the total impurity should be NMT1.0%, preferably NMT 0.75% and most preferably NMT 0.60%.

Example 21D

The tablets prepared in Example 21A (Test Formulation 1 or T1) andExample 21B (Test Formulation 2 or T2) containing nintedanib dilaurylsulfate (equivalent to 100 mg of nintedanib free base) were administeredto six (6) healthy subjects in a fasted state along with thecommercially available OFEV® capsules (Reference) containing 120.4 mg ofnintedanib esylate (equivalent to 100 mg of nintedanib free base) in asingle-center, single-dose study. This administration was an open-label,randomized, 3-treatment, 3-sequence, 3-period crossover bioavailabilitystudy in healthy subjects under fasted conditions. All subjects wererandomized to the sequences as shown in the following table with awashout period of 7 days between the periods.

Sequence Period I Period II Period III 1 Rfast T1fast T2fast 2 T2fastRfast T1fast 3 T1fast T2fast Rfast * Rfast: Reference under fastedcondition; T1fast: Test 1 under fasted condition; T2fast: Test 2 underfasted condition

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 48 hours afterdosing. AUC₀₋₂₄, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults of the study were summarized in the following tables.Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following tables:

The Pharmacokinetic Parameters for Reference and Test Formulations (100mg dose) Treatment Parameters Mean Ref C_(max) (ng/mL) 17.5 AUC_(0-t)(ng · h/mL) 143 AUC_(0-∞) (ng · h/mL) 155 Ex 21A (T1) C_(max) (ng/mL)15.5 AUC_(0-t) (ng · h/mL) 133 AUC_(0-∞) (ng · h/mL) 144 Ex 21B (T2)C_(max) (ng/mL) 13.3 AUC_(0-t) (ng · h/mL) 114 AUC_(0-∞) (ng · h/mL) 123

The Comparisons between Ex 21A (T1) vs. Reference and Ex 21B (T2) vs.Reference Comparisons Parameters Geometric Mean Ratios T1~Ref C_(max)92.29% (ng/mL) AUC_(0-t) 91.97% (ng · h/mL) AUC_(0-∞) 91.52% (ng · h/mL)T2~Ref C_(max) 77.82% (ng/mL) AUC_(0-t) 79.45% (ng · h/mL) AUC_(0-∞)79.29% (ng · h/mL)

The individual subject data obtained from the study is as follows:

Reference Drug (OFEV ®) under fasted condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 Mean SD CV % 0 0 0.133 0.115 0.147 0 0.1120.0845 0.0667 78.90 0.5 1.72 0.196 0.00 5.91 6.50 7.54 3.64 3.39 92.9 14.04 4.93 5.04 15.40 3.23 13.70 7.72 5.36 69.3 1.5 6.54 6.96 3.62 13.302.34 23.80 9.43 8.00 84.9 2 8.44 3.95 2.54 10.90 2.16 19.70 7.95 6.7284.5 3 8.41 6.50 1.45 18.10 22.90 13.30 11.8 7.90 67.1 4 9.01 9.54 1.5225.40 14.60 13.80 12.3 7.90 64.3 6 7.69 8.30 14.40 13.60 11.70 10.7011.1 2.7 24.6 8 4.60 4.83 7.89 7.73 6.49 6.45 6.33 1.39 22 10 3.10 2.843.65 5.28 4.74 4.58 4.03 0.97 24.3 12 2.26 2.51 2.64 3.85 3.38 3.35 3.000.61 20.60 24 1.33 1.15 1.08 1.75 1.56 1.85 1.45 0.31 21.8 48 0.4770.483 0.454 0.758 0.572 0.556 0.55 0.112 20.4

Example 21A (T1) Drug under fasted condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 Mean SD CV % 0 0.11 0 0 0 0.18 0.1990.0815 0.0941 115.43 0.5 1.41 1.34 0.00 0 0.279 0.444 0.579 0.64 110.6 10.97 2.35 0.119 0.245 3.61 3.31 1.77 1.54 86.9 1.5 0.891 2.05 0.245 3.745.10 3.39 2.57 1.84 71.6 2 1.16 3.51 1.11 4.21 4.37 4.80 3.19 1.65 51.603 7.80 10.20 0.843 9.30 8.07 15.30 8.59 4.67 54.4 4 17.70 13.80 5.4419.60 16.00 18.40 15.2 5.2 34.1 6 9.59 8.20 7.51 16.40 13.50 13.40 11.43.5 30.8 8 5.79 4.99 3.09 9.15 6.93 6.89 6.14 2.05 33.4 10 4.12 3.542.20 5.25 4.70 4.35 4.03 1.06 26.4 12 3.09 2.46 1.92 3.78 4.02 3.29 3.090.79 25.6 24 1.83 1.08 0.716 1.84 1.69 1.56 1.45 0.45 31.4 48 0.652 0.450.269 0.548 0.462 0.641 0.504 0.143 28.4

Example 21B (T2) Drug under fasted condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 Mean SD CV % 0 0.143 0 0 0.173 0.13 00.0743 0.0826 111.1 0.5 0.149 0 0.00 0.192 0.369 0.00 0.118 0.149 126. 10.165 0.00 0.177 0.215 1.37 0.319 0.374 0.499 133.2 1.5 0.196 0.00 0.3680.409 0.79 0.967 0.455 0.363 79.7 2 0.527 1.72 1.16 1.74 0.816 2.63 1.430.76 53.0 3 4.80 3.85 1.93 5.07 4.07 1.87 3.60 1.39 38.6 4 6.46 12.109.91 9.95 9.14 15.40 10.5 3.0 28.7 6 5.49 18.80 11.90 10.00 17.10 8.8112.0 5.1 42.2 8 3.00 10.30 4.35 5.17 8.53 4.39 5.96 2.82 47.4 10 2.346.41 2.87 3.24 5.90 2.62 3.90 1.78 45.7 12 1.98 4.85 2.14 2.52 4.23 2.333.01 1.22 40.4 24 0.998 1.66 1.04 1.20 1.56 1.16 1.27 0.28 21.7 48 0.3650.54 0.35 0.518 0.656 0.347 0.463 0.128 27.7A graph of the mean plasma profiles provided in this Example is shown inFIG. 6.

Example 22

Nintedanib dilauryl sulfate capsules were prepared by manually blending2386 mg of nintedanib dilauryl sulfate (powder) prepared according tothe procedure of Example 21 with 468 mg of croscarmellose sodium and2122 mg of lactose anhydrous. The blend was passed through a 40 meshscreen. 2122 mg of microcrystalline cellulose (PH102), 390 mg ofpoloxamer 188 and 234 mg of hydroxypropyl cellulose (HPC-H) were passedthrough a 40 mesh screen and mixed with the blend. 78 mg of magnesiumstearate was passed through a 40 mesh screen and added to the blend. Thedried solid blend was filled into size 1 hard gelatin capsule.

The composition of the capsule content is as follows:

mg wt % Nintedanib dilauryl sulfate, 59.64 30.58 (EQ to 30 mg base)Croscarmellose sodium 11.70 6.00 Lactose anhydrous 53.05 27.21Microcrystalline cellulose PH102 53.06 27.21 Poloxamer 188 9.75 5.00Hydroxypropyl cellulose (HPC-H) 5.85 3.00 Magnesium stearate 1.95 1.00Total 195.00 100.00

Example 23

A nintedanib dilauryl sulfate capsule dosage form was prepared by mixing2386 mg of the nintedanib dilauryl sulfate prepared according to theprocedure of Example 21 (powder, passed through 80 mesh screen) with amixture of 4649 mg of medium chain triglycerides (Miglyol 812N), 1920 mgof diethylene glycol monoethyl ether (Transcutol HP), 10 mg of butylatedhydroxytoluene (BHT), and 1200 mg of lecithin to obtain uniformdispersion. 1836 mg of hard fat (Gelucire 43/01) was melted in waterbath (50° C.) and added into the dispersion to obtain a uniformsuspension (semi-solid). The semi-solid suspension was filled into size1 hard gelatin capsule.

The composition of the capsule content is as follows:

mg wt % Nintedanib dilauryl sulfate, 59.64 19.88 (EQ to 30 mg base)Medium Chain Triglycerides, NF 116.22 38.74 Hard Fat 45.90 15.30Diethylene glycol monoethyl ether 48.00 16.00 Butylated hydroxytoluene0.24 0.08 Lecithin 30.00 10.00 Total 300.00 100.00

Example 24

The capsules prepared in Examples 22 and 23 containing nintedanibdilauryl sulfate (equivalent to 30 mg of nintedanib free base) wereadministered to six (6) healthy adult beagle dogs in a fasted statealong with an equivalent 30 mg capsule prepared from OFEV® capsule, 100mg. (obtained by collecting the content from commercially available 100mg OFEV® capsules containing 120.40 mg of nintedanib esylate andrefilling into new capsules in which each content is equivalent to 30 mgof nintedanib free base) in a single-center, single-dose study. Bloodsamples were drawn before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6,8, 12, 24 and 36 hours after dosing. The mean nintedanib plasma valueswere determined as follows:

Capsule Prepared Capsule Prepared According to the According to theREFERENCE Procedure of Procedure of (OFEV ®) Example 22 (T1) Example 23(T2) (R) AUC_(0-t) 549.12 619.63 349.47 (ng · hr/mL) C_(max) 64.00 66.7531.98 (ng/mL)

A graph of the mean plasma profiles is shown in FIG. 7.

The individual data from the study is shown in the following tables:

C_(max) (ng/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 38.16 10.1828.59 31.85 23.30 59.78 31.98 16.57 51.82 Ex 22 59.43 66.08 52.50 73.1866.63 66.19 64.00 7.12 11.12 Ex 23 49.48 86.93 50.35 94.11 63.12 56.5366.75 19.19 28.74

AUC_(0-t) (ng · hr/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 391.06142.18 228.30 402.56 323.60 609.13 349.47 161.42 46.2 Ex 22 464.36598.41 372.25 840.45 446.46 572.80 549.12 165.45 30.1 Ex 23 629.37696.53 499.95 1070.95 412.54 408.45 619.63 249.60 40.3

Reference (OFEV ®) Time Blood concentration (ng/mL) (hr) 101 102 201 202301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA 0.5 10.24 4.3514.66 BLQ BLQ BLQ 9.75 5.17 53.0 1 21.61 5.77 25.40 BLQ BLQ BLQ 17.5910.42 59.2 1.5 30.18 5.60 25.39 14.24 13.90 14.19 17.25 8.93 51.8 234.02 6.23 27.86 23.24 23.30 42.37 26.17 12.18 46.5 2.5 38.16 5.61 24.9425.15 21.38 42.02 26.21 12.98 49.5 3 32.18 5.75 24.01 27.36 21.74 50.2626.88 14.53 54.1 4 37.11 6.34 28.59 31.85 23.23 50.48 29.60 14.70 49.7 534.78 8.38 26.33 31.19 18.76 55.87 29.22 16.11 55.1 6 29.99 10.18  22.3630.65 16.84 59.78 28.30 17.29 61.1 8 23.00 8.34 15.85 27.99 17.79 39.5822.09 10.85 49.1 12 12.90 3.94  7.58 18.21 10.77 14.17 11.26 5.04 44.724  1.79 6.26 BLQ  2.01 4.95 7.02 4.41 2.40 54.6 36 BLQ BLQ BLQ BLQ 1.971.63 1.80 0.24 13.4

Capsule Prepared as in Example 22 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA0.5 BLQ 2.26 18.72 11.48 32.50 BLQ 16.24 12.76 78.6 1 BLQ 8.09 29.4540.31 55.41 1.88 27.03 22.24 82.3 1.5 2.30 32.72 39.48 64.58 63.59 8.5935.21 26.40 75.0 2 13.96 45.57 43.15 60.71 66.63 12.02 40.34 22.97 56.92.5 26.62 51.25 40.76 65.23 63.18 31.10 46.35 16.23 35.0 3 32.71 56.7446.59 69.56 58.40 38.55 50.43 13.71 27.2 4 30.21 58.52 52.50 73.18 54.1156.49 54.17 13.88 25.6 5 59.43 66.08 43.45 68.21 49.68 66.19 58.84 10.1517.3 6 40.91 51.72 38.58 64.09 38.22 65.08 49.77 12.49 25.1 8 29.6635.51 26.23 57.74 25.74 45.81 36.78 12.70 34.5 12 13.93 18.46  9.5130.27 11.83 18.18 17.03 7.38 43.3 24 4.60 4.92 BLQ  2.37 BLQ 2.32 3.551.40 39.5 36 1.96 BLQ BLQ BLQ BLQ BLQ 1.96 NA NA

Capsule Prepared as in Example 23 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA0.5 BLQ 29.69 1.94 8.79 41.33  2.03 16.76 17.83 106.4  1 BLQ 55.37 8.4244.56 50.28 15.00 34.72 21.48 61.9 1.5 25.94 58.79 11.04 62.32 55.6624.78 39.75 21.74 54.7 2 41.69 60.44 21.67 65.33 51.42 37.65 46.37 16.0734.7 2.5 44.60 69.23 32.96 73.12 52.64 39.85 52.07 16.17 31.1 3 49.3367.20 35.12 74.95 63.12 47.50 56.20 14.75 26.2 4 46.16 86.93 50.35 86.9255.67 56.53 63.76 18.33 28.8 5 49.48 64.56 47.24 94.11 38.86 56.09 58.3919.52 33.4 6 46.08 55.12 41.31 75.23 35.02 46.04 49.80 14.10 28.3 835.68 37.34 26.44 62.18 24.61 32.95 36.53 13.54 37.1 12 23.96 18.1114.63 36.74  9.32 16.32 19.85 9.55 48.1 24 4.83  3.05 5.19 7.30 BLQ BLQ5.09 1.74 34.3 36 2.47 BLQ 2.90 4.29 BLQ BLQ 3.22 0.95 29.6

Example 25

A nintedanib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   -   a. 17 g of nintedanib esylate was added to a co-solvent of ethyl        acetate/10% aqueous NaHCO₃ (510 mL/170 mL) (30V/10V) and stirred        at 40° C. for 1 hour;    -   b. The organic layer of the reaction mass of step (a) was        separated and washed twice with 170 mL of purified water        (10V×2);    -   c. The organic extracts of step (b) were combined and        concentrated to obtain nintedanib free base as a yellow powder        (13.4 g, 95% yield);    -   d. 1340 mL of anhydrous ethanol (100V) was added to the 13.4 g        of nintedanib free base and the mixture was stirred at 60° C.;    -   e. An SLS solution was prepared by adding 7.16 g of SLS (1 molar        equivalent to the nintedanib) to 40.2 mL of methanol (3V) and        2.3 mL of 12 N HCl (1.1 molar equivalent) and stirred at room        temperature for 10 minutes and adding 10 mL of a 10% aqueous        NaHCO₃ solution and stirring at room temperature for 5 minutes;    -   f. The SLS solution of step (e) was added to the mixture of        step (d) and stirred at 60° C. for 1 hour;    -   g. The reaction mass of step (f) was concentrated and 268 mL of        ethyl acetate (20V) is added and the resulting reaction mixture        was washed with 134 mL of purified water (10V×3);    -   h. The organic extracts of step (g) were combined, concentrated        and the solids collected and vacuum dried at 40° C. for 16 hours        to obtain 16.3 g of nintedanib monolauryl sulfate as a yellow        powder which was exhibited a chromatographic purity 100% and a        yield of 81.5%.

The nintedanib monolauryl sulfate may be used to prepared oral dosagessuch as those described in Examples 22 and 23.

Example 25A

The solubility of the nintedanib lauryl sulfate salts prepared inExample 21 and 25 and a commercially available sample of nintedanibesylate was measured by adding the sample to 5-20 mL of the designatedmedium at room temperature and shaking or stirring for at least 18 hoursto obtain a saturated condition. The reaction mass was filtered and thefiltrate solution was measured by HPLC. The results of the solubilitymeasurements are as follows:

Nintedanib Nintedanib Nintedanib Dilauryl Monolauryl Esylate SulfateSulfate pH condition (μg/mL) (μg/mL) (μg/mL) 0.1N HCl, pH = 1.0 106,60027 1081.8 0.05M acetate buffer, 6260 4.3 0 pH = 4.5 0.05M phosphatebuffer, 2.2 660 0 pH = 6.8

Example 25B

The impurity and stability of the nintedanib lauryl sulfate saltsprepared in Example 21 and 25 was measured using the HPLC methodsoutlined in Example 21C.

The test sample were prepared by respectively weighing about 29.88 mg ofnintedanib monolauryl sulfate or 39.76 mg of nintedanib dilauryl sulfate(equivalent to 20 mg of Nintedanib) and transfer into a 20-mL ambervolumetric flask, adding 16 mL of diluent (methanol), sonicating forabout 5 minutes and stirring at 800 rpms for about 5 minutes until fullydissolved. Additional diluent is added so the test sample isapproximately 1.0 mg of nintedanib per mL.

The following results were obtained:

0.23 0.59 0.92 1.10 1.34 1.36 1.38 1.14 1.44 RRT % Impurity Ex 21Initial 0.02 0.02 0.03 40° C./75% 0.02 0.02 0.03 R.H. 1 month Ex 25Initial 0.26 0.09 0.09 0.04 40° C./75% 0.25 0.18 0.11 0.01 0.04 R.H. 1month

The above data demonstrates the nintedanib dilauryl sulfate is morestable than the monolauryl sulfate and both the dilauryl and monolaurylsulfate salts of the present invention have NMT 0.5% of any individualimpurity, preferably NMT 0.35% of any individual impurity and mostpreferably NMT 0.30% of any individual impurity and the total impurityshould be NMT 1.0%, preferably NMT 0.75% and most preferably NMT 0.60%.

Example 26

A nilotinib dilauryl sulfate salt was prepared by the following generalprocedure:

-   -   a. 100 mL of methanol (10V) was added to 10 g of nilotinib HCl        and stirred at room temperature;    -   b. 1.57 mL of 12N HCl (1.1 molar equivalent) was added to the        mixture of step (a) and stirred at 50-55° C. for 2 hours;    -   c. The mixture of step (b) was distilled under vacuum and the        residue was stirred with 100 mL of hexane (10V) for 30 minutes;    -   d. The solids of step (c) were isolated by filtration, washed        with hexane and dried in a vacuum at 40° C. for 3 hours to        obtain 10.8 g of nilotinib dihydrochloride salt as a golden        yellow powder (yield 98%);    -   e. 216 mL of methanol (20V) was added to the 10.8 g of nilotinib        dihydrochloride from step (d) and the mixture was stirred at        50-55° C.;    -   f. 9.76 g of SLS (2 molar equivalents) was added to 54 mL of        methanol (5V) and the resulting mixture was added to the mixture        of step (e) and stirred at 50-55° C. for 3 hours;    -   g. The reaction mixture of step (f) was concentrated, 324 mL of        ethyl acetate (30V) was added and the resulting reaction mixture        was washed with 216 mL of purified water for three times        (20V×3);    -   h. The organic extracts of step (g) were combined, concentrated        and dried in a vacuum at 40° C. for 6 hours to obtain crude        nilotinib dilauryl sulfate;    -   i. The crude nilotinib dilauryl sulfate was combined with 108 mL        of hexane (10V) and stirred for 30 minutes;    -   j. The solids from the reaction mixture of step (i) were        isolated by filtration, washed with hexane and dried in a vacuum        at 40° C. for 16 hours to obtain 10.6 g of nilotinib dilauryl        sulfate as a yellow powder which was exhibited a chromatographic        purity 99.98% and a yield of 91%.

Example 27

A nilotinib dilauryl sulfate salt was prepared by the procedure ofExample 26 wherein 30 g of nilotinib HCl and 4.71 mL of 12 N HCl wereused to obtain 32.4 g of nilotinib dihydrochloride (yield 98%) and the32.4 g of nilotinib dihydrochloride was combined with 29.3 g of SLS toobtain 48.5 g of nilotinib dilauryl sulfate (90% yield) with achromatographic purity of 99.97%.

Example 28

A nilotinib dilauryl sulfate salt was prepared by the following generalprocedure:

-   -   a. 768 mL of methanol (30V) was added to 25.6 g of nilotinib HCl        and stirred at room temperature;    -   b. 4.02 mL of 12N HCl (1.1 molar equivalent) was added to the        mixture of step (a) and stirred at 50-55° C. for 2 hours;    -   c. The mixture of step (b) was distilled under vacuum and the        residue was stirred with 256 mL of hexane (10V) for 30 minutes;    -   d. The solids of step (c) were isolated by filtration, washed        with hexane and dried in a vacuum at 40° C. for 3 hours to        obtain 25.7 g of nilotinib dihydrochloride salt as a golden        yellow powder (yield 92%);    -   e. 514 mL of methanol (20V) was added to the 25.7 g of nilotinib        dihydrochloride from step (d) and the mixture was stirred at        50-55° C.;    -   f. 23.2 g of SLS (2 molar equivalents) was added to 128.5 mL of        methanol (5V) and the resulting mixture was added to the mixture        of step (e) and stirred at 50-55° C. for 3 hours;    -   g. The reaction mixture of step (f) was concentrated, 771 mL of        ethyl acetate (30V) was added and the resulting reaction mixture        was washed with 514 mL of purified water for three times        (20V×3);    -   h. The organic extracts are combined, concentrated and dried in        a vacuum at 40° C. for 6 hours to obtain crude nilotinib        dilauryl sulfate;    -   i. The crude nilotinib dilauryl sulfate was combined with 257 mL        of hexane (10V) and stirred for 30 minutes;    -   j. The solids from the reaction mixture of step (i) were        isolated by filtration, washed with hexane and dried in a vacuum        at 40° C. for 16 hours to obtain 36.5 g of nilotinib dilauryl        sulfate as a golden yellow powder which was exhibited a        chromatographic purity 99.93% and a yield of 85%.

Example 29

The nilotinib dilauryl sulfate prepared in Examples 26, 27 and 28 may beused to prepare oral dosages such as those described in Examples 3, 4,9, 15, 18, 19, 22, 23, 30, 31, 33, 34, 37 or 39.

Example 30

Nintedanib monolauryl sulfate capsule dosage form was prepared by wetgranulating 1,793 mg of nintedanib monolauryl sulfate prepared accordingto the procedure of Example 25 with 600 mg of poloxamer 407, 480 mg ofpoloxamer 188 and 1,600 mg of alcohol dehydrated in a container, heatedat 70° C. and mixed for 10 min. A powder mixture of 600 mg of lactoseanhydrous, 1,747 mg of microcrystalline cellulose PH102 (part I) and 300mg of sodium starch glycolate (part I) has been passed through a 40 meshsieve were added into the nintedanib monolauryl sulfate granules andmixed. The resulting mixture was dried in the oven at 70° C. toevaporate the alcohol. The dried mixture was combined with 300 mg ofsodium starch glycolate (part II), 120 mg of colloidal silicon dioxideand 800 mg of microcrystalline cellulose PH102 (part II) that has beenpassed through a 40 mesh sieve and dry mixed. The resulting dry mixturewas passed through 40 mesh sieve and collected in a suitable container.60 mg of magnesium stearate was passed through a 40 mesh sieve and addedto the container and mixed to obtain a final blend. The dry solid finalblend was filled into size 1 hard gelatin capsules.

The composition of the capsule content was as follows:

mg wt % Nintedanib monolauryl sulfate, 44.82 26.36 NTB-1LS (EQ to 30 mgbase) Lactose anhydrous 15.00 8.82 Microcrystalline cellulose (part I)43.68 25.69 Sodium starch glycolate (part I) 7.50 4.41 Poloxamer 40715.00 8.82 Poloxamer 188 12.00 7.06 Sodium starch glycolate (part II)7.50 4.41 Colloidal silicon dioxide 3.00 1.76 Microcrystalline cellulose(part II) 20.00 11.76 Magnesium stearate 1.50 0.88 Total 170.00 100.00Alcohol dehydrated 40.00 N/A

Example 31

A nintedanib monolauryl sulfate capsule dosage form was prepared bymixing 2,441 mg of medium chain triglycerides (Miglyol 812N), 680 mg ofdiethylene glycol monoethyl ether (Transcutol HP), 6 mg of butylatedhydroxytoluene (BHT), and 680 mg of lecithin to obtain uniformdispersion. 1200 mg of hard fat (Gelucire 43/01) was melted in waterbath (50° C.) and added into the uniform dispersion to obtain uniformsuspension (semi-solid). 1,793 mg of nintedanib monolauryl sulfateprepared according to the procedure of Example 25 was passed through 80mesh sieve and added into the suspension to obtain uniform suspensionand/or coagulate into semi-solid. The semi-solid suspension was filledinto size 1 hard gelatin capsule.

The composition of the capsule content was as follows:

mg wt % Nintedanib monolauryl sulfate, 44.82 26.36 NTB-1LS (EQ to 30 mgbase) Medium Chain Triglycerides, NF 61.02 35.89 Hard Fat 30.00 17.65Diethylene glycol monoethyl ether 17.00 10.00 Butylated hydroxytoluene0.16 0.09 Lecithin 17.00 10.00 Total 170.00 100.00

Example 32

The capsules prepared in Examples 30 and 31 containing nintedanibmonolauryl sulfate (equivalent to 30 mg of nintedanib free base) wereadministered to six (6) healthy adult beagle dogs in a fasted statealong with an equivalent 30 mg capsule prepared from OFEV® capsule, 100mg. (obtained by collecting the content from commercially available 100mg OFEV® capsules containing 120.40 mg of nintedanib esylate andrefilling into new capsules in which each content is equivalent to 30 mgof nintedanib free base) in a single-center, single-dose study. Bloodsamples were drawn before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6,8, 12, 24 and 36 hours after dosing. The mean nintedanib plasma valueswere determined as follows:

Capsule Prepared Capsule Prepared According to the According to theREFERENCE Procedure of Procedure of (OFEV ®) Example 30 (T1) Example 31(T2) (R) AUC_(0-t) 470.92 522.07 313.92 (ng · hr/mL) C_(max) 40.81 46.1026.09 (ng/mL)

A graph of the mean plasma profiles is shown in FIG. 8.

The individual data from the study is shown in the following tables:

C_(max) (ng/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 36.23 20.2022.57 49.15 12.45 15.93 26.09 13.94 53.42 Ex 30 17.63 51.91 42.34 30.0218.32 84.62 40.81 25.32 62.04 Ex 31 33.41 52.08 40.03 56.21 36.26 58.6046.10 10.85 23.54

AUC_(0-t) (ng · hr/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 420.87326.13 311.61 499.02 143.17 182.71 313.92 135.81 43.26 Ex 30 268.40571.31 487.05 417.71 262.23 818.83 470.92 209.18 44.42 Ex 31 512.55666.21 522.56 508.13 408.65 514.33 522.07 82.44 15.79

Reference (OFEV ®) Time Blood concentration (ng/mL) (hr) 101 102 201 202301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA 0.5 23.00 1.309.60 BLQ 3.64 BLQ 9.38 9.73 103.66 1 29.25 4.93 17.88 5.14 5.92 0.5510.61 10.82 101.98 1.5 31.34 16.93 19.54 36.44 7.66 9.66 20.26 11.5557.02 2 30.59 15.57 19.23 42.73 6.15 11.90 21.03 13.42 63.80 2.5 30.5016.04 16.78 49.15 7.61 15.93 22.67 14.92 65.83 3 36.23 17.60 22.57 41.958.01 13.91 23.38 13.19 56.42 4 35.73 18.04 18.88 31.04 7.97 14.11 20.9610.47 49.96 5 34.32 20.20 17.58 39.52 8.31 15.52 22.57 11.91 52.75 632.43 19.21 18.06 36.02 7.22 15.19 21.35 10.87 50.91 8 19.39 16.69 14.7528.42 12.45 8.68 16.73 6.79 40.61 12 11.82 10.60 12.10 14.00 4.92 7.0110.08 3.43 34.03 24 3.37 6.01 3.39 5.53 1.11 1.27 3.45 2.05 59.58 361.59 1.91 1.30 2.10 0.75 0.58 1.37 0.62 44.91

Capsule Prepared as in Example 30 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA0.5 9.97 18.56 5.45 3.83 6.69 8.82 8.89 5.23 58.88 1 16.49 17.04 34.3222.62 17.48 47.91 25.98 12.68 48.81 1.5 15.63 51.91 36.40 27.94 16.0184.62 38.75 26.27 67.79 2 14.11 51.85 38.96 27.33 17.81 80.78 38.4724.96 64.87 2.5 16.07 51.73 40.72 27.49 16.47 73.48 37.66 22.40 59.48 317.31 50.30 32.93 26.79 18.32 79.26 37.49 23.74 63.34 4 17.63 42.7842.34 30.02 16.66 72.54 37.00 20.80 56.22 5 16.26 39.46 33.71 25.3017.96 68.97 33.61 19.49 57.99 6 16.56 37.72 33.15 26.43 16.67 56.0231.09 14.90 47.94 8 15.90 28.45 26.50 21.37 14.09 43.57 24.98 10.7242.90 12 11.05 16.19 16.92 12.99 8.63 24.26 15.01 5.50 36.63 24 1.665.56 3.04 5.70 2.73 4.08 3.79 1.62 42.66 36 0.77 2.94 1.23 1.94 1.262.05 1.70 0.78 45.69

Capsule Prepared as in Example 31 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA0.5 27.55 BLQ 4.52 BLQ BLQ 10.52 14.20 11.95 84.17 1 32.95 4.94 6.45 BLQ6.37 44.18 18.98 18.32 96.57 1.5 33.39 23.15 26.87 0.61 18.07 58.6026.78 19.13 71.44 2 32.05 35.21 32.89 1.63 24.00 47.80 28.93 15.43 53.332.5 32.30 39.22 37.73 6.08 25.88 44.05 30.88 13.65 44.22 3 33.41 46.1737.30 14.05 27.52 45.06 33.92 12.01 35.42 4 30.71 52.08 36.37 29.2931.50 49.41 38.23 10.02 26.22 5 30.07 47.64 37.49 39.78 30.99 40.0337.67 6.51 17.28 6 30.31 50.20 40.03 56.21 36.26 37.47 41.75 9.62 23.058 26.87 36.41 31.90 33.46 26.62 28.77 30.67 3.92 12.77 12 20.45 20.9419.28 18.73 14.05 14.69 18.02 2.95 16.35 24 3.61 8.92 3.77 5.74 2.942.01 4.50 2.49 55.46 36 2.44 3.57 1.88 3.48 1.08 0.73 2.20 1.19 54.16

Example 33

Dasatinib monolauryl sulfate capsule dosage form was prepared by wetgranulating 1,865 mg of dasatinib monolauryl sulfate prepared accordingto the procedure of Example 12 with 750 mg of poloxamer 407, 600 mg ofpoloxamer 188 and 2,000 mg of alcohol dehydrated in a suitablecontainer, heated to 70° C. and mixed for 10 min. 600 mg of lactoseanhydrous, 1,405 mg of microcrystalline cellulose PH102 and 300 mg ofsodium starch glycolate (part I) were passed through a 40 mesh sieve andadded the dasatinib monolauryl sulfate granules and mixed. The resultingmixture was dried in an oven at 50° C. to evaporate the alcohol. Thedried mixture was combined with 300 mg of sodium starch glycolate (partII) and 120 mg of colloidal silicon dioxide that has been passed througha 40 mesh sieve and mixed. The resulting mixture was passed through 40mesh sieve and collected in suitable container. 60 mg of magnesiumstearate was passed through a 40 mesh sieve and added to the containerand mixed to obtain a final blend. The dry solid final blend was filledinto size 1 hard gelatin capsule.

The composition of the capsule content was as follows:

mg wt % Dasatinib monolauryl sulfate, 37.3 31.1 dasatinib-1LS Lactoseanhydrous 12.0 10.0 Microcrystalline cellulose 28.1 23.4 Sodium starchglycolate (part I) 6.0 5.0 Poloxamer 407 15.0 12.5 Poloxamer 188 12.010.0 Sodium starch glycolate (part II) 6.0 5.0 Colloidal silicon dioxide2.4 2.0 Magnesium stearate 1.2 1.0 Total 120.0 100.0 Alcohol dehydrated40.0 N/A

Example 34

Dasatinib dilauryl sulfate capsule dosage form was prepared by wetgranulating the 2,520 mg of dasatinib dilauryl sulfate preparedaccording to the procedure of Example 13 with 750 mg of poloxamer 407,600 mg of poloxamer 188 and 1000 mg of alcohol dehydrated in a suitablecontainer. 300 mg of lactose anhydrous, 1,050 mg of microcrystallinecellulose PH102 and 300 mg of sodium starch glycolate (I) were passedthrough a 40 mesh sieve and added to the dasatinib dilauryl sulfategranules and mixed. The resulting mixture was dried in the oven at 50°C. to evaporate the alcohol. The dried mixture was combined with 300 mgof sodium starch glycolate (II) and 120 mg of colloidal silicon dioxidethat has been passed through a 40 mesh sieve and mixed. The resultingmixture was passed through 40 mesh sieve and collected in a suitablecontainer. 60 mg of magnesium stearate was passed through a 40 meshsieve and added to the container and mixed to obtain a final blend. Thedry solid final blend was filled into size 1 hard gelatin capsule.

The composition of the capsule content was as follows:

mg wt % Dasatinib dilauryl sulfate, 50.4 42.0 dasatinib-2LS Lactoseanhydrous 6.0 5.0 Microcrystalline cellulose 21.0 17.5 Sodium starchglycolate (part I) 6.0 5.0 Poloxamer 407 15.0 12.5 Poloxamer 188 12.010.0 Sodium starch glycolate (part II) 6.0 5.0 Colloidal silicon dioxide2.4 2.0 Magnesium stearate 1.2 1.0 Total 120.0 100.0 Alcohol dehydrated20.0 N/A

Example 35

The capsules prepared in Examples 33 and 34 containing dasatinibmonolauryl sulfate or dasatinib dilauryl sulfate were administered tosix (6) healthy adult beagle dogs in a fasted state along with anequivalent 25 mg capsule obtained by dividing the content from acommercially available 50 mg Sprycel® film coated tablet (containing 50mg of dasatinib) into 2 capsules in a single-center, single-dose study.Blood samples were drawn before dosing and at 0.33, 0.67, 1, 1.5, 2, 3,4, 6, 8, 12 and 24 hours after dosing. The dose which in analyses wasnormalized to 25 mg dasatinib monohydrate for test drug and 25 mgdasatinib for Sprycel® in this example. The 25 mg normalized meandasatinib plasma values were determined as follows:

Capsule Prepared Capsule Prepared According to the According to theREFERENCE Procedure of Procedure of (Sprycel ®) Example 33 (T1) Example34 (T2) (R) AUC_(0-t) 161.81 209.06 22.41 (ng · hr/mL) C_(max) 52.1276.28 3.91 (ng/mL)

A graph of the normalized mean plasma profiles is shown in FIG. 9.

The normalized individual data from the study is shown in the followingtables:

C_(max) (ng/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 1.61 1.621.63 2.03 0.65 15.92 3.91 5.90 150.89 Ex 33 39.77 94.41 22.26 53.7063.64 38.97 52.12 25.06 48.08 Ex 34 86.69 77.07 26.64 77.95 169.56 19.7576.28 53.80 70.53

AUC_(0-t) (ng · hr/mL) 101 102 201 202 301 302 Mean SD CV (%) Ref 10.4919.81 9.03 11.61 8.11 75.42 22.41 26.30 117.37 Ex 33 131.33 221.27 89.60181.24 167.82 179.59 161.81 45.62 28.20 Ex 34 182.01 188.79 126.64197.76 441.39 117.78 209.06 118.64 56.75

Reference (Sprycel ®) Time Blood concentration (ng/mL) (hr) 101 102 201202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA 0.33 0.120.27 1.03 BLQ 0.20 1.06 0.54 0.47 87.54 0.67 0.60 0.74 0.86 0.02 0.393.58 1.03 1.28 124.47 1 0.45 0.57 0.86 0.03 0.57 7.36 1.64 2.81 171.811.5 0.62 0.73 0.92 0.05 0.65 15.92 3.15 6.26 198.86 2 1.61 0.57 1.070.12 0.55 13.12 2.84 5.06 178.31 3 0.55 0.24 1.38 0.65 0.23 10.15 2.203.92 178.07 4 0.54 0.22 1.63 2.03 0.15 10.58 2.53 4.02 159.23 6 0.430.12 0.52 0.56 0.09 6.93 1.44 2.70 186.96 8 0.50 0.24 0.24 0.47 0.272.78 0.75 1.00 132.96 12 0.56 0.90 0.11 0.52 0.22 0.57 0.48 0.28 58.7024 0.06 1.62 0.05 0.12 0.62 0.04 0.42 0.63 151.06

Capsule Prepared as in Example 33 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA NA0.33 13.05 0.32 21.62 0.03 BLQ BLQ 8.75 10.51 120.03 0.67 21.78 59.4819.71 38.42 1.68 0.73 23.63 22.49 95.18 1 33.92 94.41 22.26 53.70 22.454.29 38.51 31.84 82.69 1.5 39.77 61.61 18.95 31.21 63.64 9.68 37.4822.03 58.79 2 34.84 49.50 14.89 27.13 61.38 18.81 34.42 18.07 52.49 322.77 27.22 12.75 20.81 24.81 38.97 24.56 8.62 35.10 4 14.22 21.06 10.7017.03 13.94 38.61 19.26 10.10 52.42 6 4.48 7.40 4.64 16.61 6.49 14.258.98 5.17 57.59 8 1.66 3.21 1.32 6.65 2.90 6.08 3.63 2.24 61.57 12 0.771.20 0.45 1.28 1.05 1.76 1.08 0.45 41.54 24 BLQ 0.22 0.04 0.06 BLQ 0.160.12 0.08 71.06

Capsule Prepared as in Example 34 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NA NA N/A0.33 0.12 1.83 0.18 BLQ BLQ 0.12 0.56 0.85 150.72 0.67 1.75 12.82 18.92BLQ 0.06 5.24 7.76 7.93 102.26 1 8.78 76.71 23.08 0.33 1.67 8.88 19.9128.97 145.55 1.5 86.69 77.07 23.90 34.10 169.56 16.75 68.01 57.39 84.382 61.68 44.63 22.48 77.95 125.34 19.75 58.64 39.62 67.56 3 26.30 25.2326.64 47.11 64.27 13.79 33.89 18.37 54.20 4 21.49 18.34 22.11 28.6851.42 16.82 26.47 12.89 48.68 6 5.43 5.35 6.08 8.59 24.54 10.85 10.147.37 72.71 8 3.00 3.07 2.76 3.96 15.23 5.10 5.52 4.84 87.64 12 1.04 0.670.81 1.47 3.11 1.56 1.44 0.89 61.54 24 0.23 0.34 BLQ BLQ 0.14 0.11 0.210.10 49.39

Example 36

A nilotinib lauryl sulfate salt was prepared by mixing 43 gm ofnilotinib hydrochloride monohydrate, 1,935 mL of anhydrous alcohol mixat 50˜55° C. To the solution, 21.23 gm of sodium lauryl sulfate [in 63.7mL of alcohol (95%) and 42.5 mL of purified water] was added. Themixture was stirred at 50˜55° C. for 30 min, room temperature for 1 hand in 0˜10° C. for 30 min. To the mixture, 1,505 mL of purified waterwas added and stirred at 0˜10° C. for 30 min. The resulting whitecrystals were collected by filtration, washed with 215 mL of 85.5%ethanol aqueous solution, to obtain nilotinib monolauryl sulfatecrude-1. The nilotinib monolauryl sulfate crude-1 was added 430 mL ofpurified water stirred 30 min, and collected by filtration, washed with430 mL of purified water, to obtain nilotinib monolauryl sulfatecrude-2. Nilotinib monolauryl sulfate crude-2 was added 430 mL of hexanestirred 30 min, and collected by filtration, washed with 215 mL ofhexane, to obtain 48 g of nilotinib monolauryl sulfate salt (82% yield)as an off-white powder with a chromatographic purity of 99.92%.

Example 37

A nilotinib monolauryl sulfate capsule dosage form was prepared bymixing 3.754 gm of nilotinib monolauryl sulfate prepared according tothe procedure of Example 36, with 12.528 gm of CAPMUL® MCM (GlycerylCaprylate/Caprate), and 3.133 gm of KOLLIPHOR® EL (polyoxyl 35 castoroil) and filling the mixture into soft gelatin capsules.

The composition of the capsule content was as follows:

mg wt % Nilotinib mono lauryl sulfate 75.06 19.35 GlycerylCaprylate/Caprate 250.31 64.52 Polyoxyl 35 Castor Oil 62.58 16.13 Total387.95 100.00

Example 38

A nilotinib dilauryl sulfate salt was prepared by mixing 25.6 gm ofnilotinib hydrochloride monohydrate, 768 mL of methanol at roomtemperature. To the solution, 4.02 mL of hydrochloric acid solution(12N) was added. The mixture was distilled out completely under vacuum.To the residue, 256 mL of hexane was added and stirred at roomtemperature for 30 min. The solid was isolated by filtration, washedwith hexane and dried in a vacuum at 40° C. for 3 hours to obtainnilotinib dihydrochloride salt as a golden yellow powder. 25.7 gm ofnilotinib dihydrochloride salt and 514 mL of methanol were mix at 50˜55°C. To the solution, 23.2 gm of sodium lauryl sulfate (in 116 mL ofmethanol) was added. The mixture was stirred at 50˜55° C. for 3 hours.The mixture was concentrated, then 771 mL of ethyl acetate was added andthe resulting reaction mass was washed with 514 mL of purified water.The organic extracts were concentrated, and dried in a vacuum at 40° C.for 6 hours to obtain crude nilotinib dilauryl sulfate salt. The crudenilotinib dilauryl sulfate salt was added to 257 mL of hexane stirred 30min. The solid was isolated by filtration, washed with hexane and driedin a vacuum at 40° C. for 16 hours to obtain 36.5 g of nilotinibdilauryl sulfate salt (85% yield) as a golden yellow powder with achromatographic purity of 99.93%.

The XRPD for the golden yellow powder nilotinib dilauryl sulfate salt isshown in FIG. 10. The XRPD was obtained using D8 Discover with GADDS(Bruker AXS Gmbh, Karlsruhe, Germany) (GADDS: General Area DiffractionDetection System) and employing the following testing condition:

-   -   Cukα₁₊₂=1.54184 Å,    -   40 kV 40 mA    -   Beam size: 1.0 mm (the collimator system allows the analysis of        1000 μm² surface areas)    -   Detector type: Vantec-2000 (14×14 cm² area and 2048×2048 pixel        density)    -   Sample to detector distance: 15.05 cm    -   300 sec/frame (The exposure time was 300 s per frame).

Example 38A

The solubility of the nilotinib monolauryl sulfate salts prepared inExamples 36 and a commercially available sample of nilotinibhydrochloride monohydrate was measured by adding the sample to 300 mL ofthe designated medium at 37° C. and shaking or stirring for at least 18hours to obtain a saturated condition. The solubility of the nilotinibdilauryl sulfate salts prepared in Examples 38 was measured by addingthe sample to 5-20 mL of the designated medium at room temperature andshaking or stirring for at least 18 hours to obtain a saturatedcondition. The reaction mass was filtered and the filtrate solution wasmeasured by HPLC. The results of the solubility measurements are asfollows:

Niliotinib Nilotinib Nilotinib Dilauryl Monolauryl HCl Sulfate SulfatepH condition (μg/mL) (μg/mL) (μg/mL) 0.1N HCl, pH = 1.0 3797.17 197.81247.86 0.05M acetate buffer, — — 0 pH = 4.5 0.05M phosphate buffer, 00.50 0 pH = 6.8

Example 39

A nilotinib dilauryl sulfate capsule dosage form was prepared by mixing8.022 gm of nilotinib dilauryl sulfate salt prepared according to theprocedure of Example 38 with 20.042 gm of CAPMUL® MCM (GlycerylCaprylate/Caprate), 5.010 gm of KOLLIPHOR® EL (polyoxyl 35 castor oil)and 0.667 gm of sodium hydrogen carbonate and filling the mixture intosoft gelatin capsules.

The composition of the capsule content was as follows:

mg wt % nilotinib dilauryl sulfate 100.25 23.79 GlycerylCaprylate/Caprate 250.31 59.39 Polyoxyl 35 Castor Oil 62.58 14.85 Sodiumhydrogen carbonate 8.33 1.97 Total 421.47 100.00

Example 40

The capsules similar to those prepared in Examples 37 and 39 butadjusted to contain a weight providing approximately equivalent to 50 mgnilotinib free base were administered to six (6) healthy adult beagledogs in a fasted state along with a capsule, obtained by dividingcommercially available 200 mg TASIGNA capsule into 4 capsules (eachcontained equivalent to 50 mg of nilotinib free base) in asingle-center, single-dose study. Blood samples were drawn before dosingand at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours after dosing.The mean nilotinib plasma values were determined as follows:

Capsule Prepared Capsule Prepared According to the According to theProcedure of Procedure of REFERENCE Example 37 Example 39 (TASIGNA)AUC₀₋₂₄ 2827.37 1053.39 754.74 (ng · hr/mL) C_(max) 675.73 396.67 171.96(ng/mL)

A graph of the mean plasma profiles is shown in FIG. 11.

The individual data from the study is shown in the following tables:

C_(max) 101 102 201 202 301 302 Mean SD CV (%) Ref 38.32 108.73 514.0721.22 281.97 67.46 171.96 192.17 111.8 Ex 37 241.14 331.19 764.011051.15 543.62 1123.29 675.73 367.17 54.3 Ex 39 505.19 273.09 344.76163.62 285.11 808.25 396.67 230.61 58.1

AUC₀₋₂₄ 101 102 201 202 301 302 Mean SD CV (%) Ref 187.46 322.80 2804.6697.84 841.82 273.84 754.74 1037.39 137.4 Ex 37 902.38 1056.24 3979.914335.56 2327.08 4363.05 2827.37 1615.80 57.1 Ex 39 1588.08 741.951796.96 685.43 1392.16 2815.74 1503.39 784.45 52.2

Reference (TASIGNA) Time Blood concentration (ng/mL) (hr) 101 102 201202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ 0 0 0 0.25 1.59 12.20BLQ BLQ BLQ BLQ 2.30 4.89 212.8 0.5 11.38 64.43 31.75 BLQ 3.68 BLQ 18.5425.45 137.3 1 38.32 108.73 396.29 BLQ 123.78 22.58 114.95 146.21 127.2 235.86 75.49 514.07 15.97 158.93 60.47 143.47 188.11 131.1 3 25.10 47.58395.32 21.22 128.74 67.46 114.23 143.14 125.3 4 17.42 37.15 399.26 15.96281.97 55.32 134.51 164.53 122.3 5 8.76 19.04 303.51 12.98 76.08 25.3274.28 114.93 154.7 6 6.15 12.67 200.15 10.35 35.42 17.45 47.03 75.70161.0 8 3.51 4.83 109.42 4.56 15.95 6.99 24.21 41.99 173.5 10 2.08 2.1260.41 2.83 7.29 3.24 13.00 23.31 179.4 12 1.24 1.88 33.61 1.42 2.29 1.697.02 13.03 185.6 24 6.31 BLQ 1.37 BLQ BLQ BLQ 1.28 2.52 197.2 Below theLimit of Quantitation (BLQ) as 0

Capsule Prepared as in Example 37 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ 0 0 00.25 BLQ BLQ BLQ 8.34 3.94 BLQ 2.05 3.46 169.2 0.5 13.34 BLQ 9.16 234.32264.04 54.38 95.87 120.58 125.8 1 184.76 176.94 242.25 862.60 451.72901.90 470.03 334.70 71.2 2 241.14 331.19 764.01 1051.15 543.62 1123.29675.73 367.17 54.3 3 156.47 250.93 640.73 709.42 216.03 676.71 441.71258.92 58.6 4 103.70 135.21 507.50 575.99 427.10 611.90 393.56 221.7356.3 5 52.93 80.89 384.47 401.68 248.45 414.15 263.76 163.91 62.1 635.13 45.15 336.42 319.93 187.23 305.82 204.95 138.11 67.4 8 15.29 18.84166.46 115.35 65.92 114.54 82.73 60.00 72.5 10 6.91 8.18 105.63 58.2718.12 61.43 43.09 39.06 90.6 12 3.62 3.55 62.16 33.29 4.18 29.53 22.7223.62 104.0 24 13.69 BLQ 2.36 BLQ BLQ BLQ 2.67 5.48 204.8 Below theLimit of Quantitation (BLQ) as 0

Capsule Prepared as in Example 39 Time Blood concentration (ng/mL) (hr)101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ 0 0 00.25 BLQ BLQ 104.70 BLQ 66.07 8.75 29.92 44.79 149.7 0.5 BLQ BLQ 344.762.65 242.80 102.05 115.38 147.21 127.6 1 160.09 BLQ 344.08 163.62 285.11435.30 231.37 155.17 67.1 2 310.06 273.09 304.78 139.21 249.98 808.25347.56 234.07 67.3 3 505.19 178.17 272.17 115.24 194.45 550.26 302.58181.98 60.1 4 157.39 108.20 227.98 78.63 186.13 379.33 189.61 107.2056.5 5 90.20 63.00 175.81 75.09 135.70 234.05 128.97 66.39 51.5 6 54.4543.26 114.93 50.43 116.42 198.08 96.26 59.63 61.9 8 21.93 17.23 68.5824.15 43.93 55.03 38.48 20.69 53.8 10 11.75 8.26 37.27 10.51 17.98 27.9518.95 11.45 60.4 12 6.06 3.64 18.61 8.57 6.03 13.84 9.46 5.67 60.0 2435.62 BLQ 434.62* BLQ BLQ BLQ 7.12 15.93 223.6 *The outlier, not forcalculation. Below the Limit of Quantitation (BLQ) as 0

Example 41

A cabozantinib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   -   a. 37 g of cabozantinib S-malate was added to a co-solvent of        (1850 mL/740 mL) of ethyl acetate/10% aqueous NaHCO₃ (50V/20V)        and stirred at 45° C. for 2 hour;    -   b. The organic layer of the reaction mixture of step (a) was        separated and washed twice with 740 mL of purified water        (20V×2);    -   c. The organic extracts of step (b) were combined and        concentrated to obtain cabozantinib free base as a white powder        (29.2 g, 100% yield);    -   d. 1022 mL of methanol (35V) was added to the 29.2 g of        cabozantinib free base and the mixture was stirred at 50-55° C.;    -   e. An SLS solution was prepared by dissolving 16.8 g of SLS (1        molar equivalent to the cabozantinib) in a co-solvent of 87.6 mL        of methanol (3V)/58.26 mL of 1 N HCl (1 molar equivalent);    -   f. The SLS solution of step (e) is added to the mixture of        step (d) and stirred at 50-55° C. for 30 minutes then adjusted        to room temperature for 1 hour;    -   g. 1460 mL of purified water (50V) was added to the reaction        mixture of step (f) and stirred at room temperature for 30        minutes;    -   h. The precipitate (crystals) of step (g) were collected by        filtration, washed with 292 mL of purified water (10V) to obtain        crude cabozantinib monolauryl sulfate;    -   i. The crude cabozantinib monolauryl sulfate was combined with        584 mL of purified water (20 V), stirred for 30 minutes, the        solids were collected by filtration, washed with 146 mL of        purified water (5 V) to obtain 41 g of cabozantinib monolauryl        sulfate as a white powder which was exhibited a UPLC        chromatographic purity 100% and a yield of 91.7%.

The solubility of the cabozantinib monolauryl sulfate prepared above wasmeasured by adding the sample to 50 mL of the designated medium at 37°C. and shaking or stirring for at least 1 hour to obtain a saturatedcondition. The reaction mass was filtered and the filtrate solution wasmeasured by HPLC. The results of the solubility measurements are asfollows:

Cabozantinib Monolauryl Sulfate pH condition (μg/mL) 0.1N HCl, pH = 1.09.87 0.05M acetate buffer, pH = 4.5 0.9 0.05M phosphate buffer, pH = 6.80.0 water 0.0

Example 42

The cabozantinib monolauryl sulfate prepared in Example 41 may be usedto prepared oral dosages such as those described in Examples 3, 4, 9,15, 18, 19, 22, 23, 30, 31, 33, 34, 37 or 39.

Example 42A

A cabozantinib monolauryl sulfate capsule dosage form was prepared by awet granulating process as follows:

-   -   (i) a granulating solution was prepared by dissolving 3.0595 g        of cabozantinib monolauryl sulfate prepared according to the        procedure of Example 41, 6.10 g of poloxamer 407 and 3.05 g of        poloxamer 188 in 300 mL of 95% alcohol;    -   (ii) 1.75 g of anhydrous lactose, 3.6405 g of microcrystalline        cellulose PH112, 1.00 g of croscarmellose sodium (Part I) and        0.20 g of colloidal silicon dioxide (Part I) were passed through        a 40 mesh sieve, blended and granulated with the granulating        solution of step (i);    -   (iii) the wet granules were passed through a 20 mesh sieve,        dried in an oven at 55° C. to evaporate the alcohol and the dry        granules were passed through a 24 mesh sieve;    -   (iv) the dried granules of step (iii) were mixed with 1.00 g of        croscarmellose sodium (Part II) and 0.10 g of colloidal silicon        dioxide (Part II);    -   (v) 0.10 g of magnesium stearate was added to the mixture of        step (iv) and blended well to obtain final blend; and    -   (vi) the dry solid final blend was filled into size 1 hard        gelatin capsule.

The composition of the capsule content is as follows:

mg wt % Cabozantinib monolauryl sulfate, 30.595 15.30 CT-1LS (EQ to 20mg free base) Poloxamer 407 61.00 30.50 Poloxamer 188 30.50 15.25Anhydrous lactose 17.50 8.75 Microcrystalline cellulose PH112 36.40518.20 Croscarmellose Sodium (Part I) 10.00 5.00 Colloidal SiliconDioxide (Part I) 2.00 1.00 Croscarmellose Sodium (Part II) 10.00 5.00Colloidal Silicon Dioxide (Part II) 1.00 0.50 Magnesium stearate 1.000.50 Total 200.00 100.00 Alcohol 95% 3.00 mL N/A

Example 42B

A cabozantinib monolauryl sulfate capsule dosage form was prepared bythe following processes:

-   -   (i) 8 mg of butylated hydroxytoluene (BHT) was dissolved a        mixture of 14.6856 g of CAPMUL® MCM (Glyceryl Caprylate/Caprate)        and 5.2112 g of KOLLIPHOR® EL (polyoxyl 35 castor oil);    -   (ii) 4.8952 g of cabozantinib monolauryl sulfate prepared        according to the procedure of Example 41 was passed through 60        mesh sieve and added into the solution of step (i) to obtain        uniform dispersion;    -   (iii) 2.40 g of hard fat (Gelucire 43/01) was melted using a        water bath at 55° C. and the melted hard fat was added to the        dispersion of step (ii) while maintaining the temperature at        55° C. and homogenized to obtain uniform suspension; and    -   (iv) the suspension of step (iii) was filled into size 3 hard        gelatin capsule.

The composition of the capsule content is as follows:

mg wt % Cabozantinib monolauryl sulfate, 30.595 18.00 CT-1LS (EQ to 20mg free base) CAPMUL ® MCM (Glyceryl Caprylate/Caprate) 91.785 53.99KOLLIPHOR ® EL (polyoxyl 35 castor oil) 32.57 19.16 Butylatedhydroxytoluene (BHT) 0.05 0.03 Hard Fat (Gelucire 43/01) 15.00 8.82Total 170.00 100.00

Example 42C

A cabozantinib malate tablet dosage form was prepared by the followingprocesses:

-   -   (i) 2.0276 g of cabozantinib malate was passed through 60 mesh        sieve and blended with 2.4864 g of microcrystalline cellulose        PH102, 1.2428 g of anhydrous lactose and 0.192 g of        croscarmellose sodium (Part I) that had been previously passed        through a 40 mesh sieve;    -   (ii) the mixture of step (i) was wet granulated with a        granulating solution prepared by dissolving 0.192 g of        hydroxypropyl cellulose EXF in 1.28 g of purified water;    -   (iii) the wet granules were passed through a 20 mesh sieve,        dried in the oven at 60° C. to evaporate the purified water and        the dry granules were passed through a 24 mesh sieve;    -   (iv) the dried and sieved granules were mixed with 0.192 g of        croscarmellose sodium (Part II) and 0.0192 g of colloidal        silicon dioxide;    -   (v) 0.048 g of magnesium stearate was added to the mixture of        step (iv) and blended well to obtain final blend; and    -   (vi) the final blend was compressed into tablets using a 6 mm        round-shaped punch and a target hardness of about 4 kp.

The composition of the tablet content is as follows:

mg wt % Cabozantinib malate, 25.345 31.68 (EQ to 20 mg free base)Microcrystalline cellulose PH102 31.08 38.85 Lactose Anhydrous 15.53519.42 Hydroxypropyl cellulose EXF 2.40 3.00 Croscarmellose Sodium (PartI) 2.40 3.00 Croscarmellose Sodium (Part II) 2.40 3.00 Colloidal SiliconDioxide 0.24 0.30 Magnesium stearate 0.60 0.75 Total 80.00 100.00Purified water 16.00 N/A

Example 42D

The following capsule formulations were prepared according to theprocedure of Example 42B. The composition of the capsules is as follows:

CT1902211 CT1902212 (mg) (mg) Cabozantinib monolauryl sulfate, 61.1961.19 CT-1LS (EQ to 40 mg free base) CAPMUL ® MCM 183.57 61.71 (GlycerylCaprylate/Caprate) KOLLIPHOR ® EL (polyoxyl 35 castor oil) 65.14 61.00Butylated hydroxytoluene (BHT) 0.10 0.10 Hard Fat (Gelucire 43/01) 30.00— Total 340.00 184.00

Example 42E

The dosage forms prepared in Examples 42A-42D (n=3) were tested using aUSP Type II Apparatus (Paddle) with 900 ml of 0.1 N HCl (with 0.5%Triton X-100) at 75 rpm, with a sinker and 37° C. The results of thisdissolution testing are as follows:

Time (min) 5 10 15 20 30 45 60 90 120 Ex Avg % 16.5 43.7 58.0 66.4 76.883.5 86.3 89.1 90.8 42A RSD % 18.2 0.8 4.1 7.7 9.4 8.0 7.4 7.0 5.9 ExAvg % 0.1 3.8 14.9 30.0 56.3 80.5 91.6 99.3 102.2 42B RSD % 42.2 28.644.6 48.8 33.4 12.2 5.1 1.4 0.5 Ex Avg % 69.7 98.0 100.6 101.8 101.7102.2 102.2 102.1 102.0 42C* RSD % 1.3 1.7 1.7 1.8 1.5 2.1 1.9 2.3 2.1Ex Avg % 0.1 4.1 19.8 34.7 53.0 67.8 75.1 81.9 85.2 42D** RSD % 31.544.0 45.5 44.0 34.9 36.5 22.8 19.0 17.6 *without a sinker **capsulewithout Gelucire 43/01

The above in vitro dissolution data demonstrates that dosage formsprepared in accordance with the present invention will release: (i) atleast 40%, preferably at least 45% and most preferably at least 50% ofthe cabozantinib after 30 minutes of testing; (ii) at least 55%,preferably at least 60% and most preferably at least 65% of thecabozantinib after 45 minutes of testing; and (iii) at least 70%,preferably at least 75% and most preferably at least 80% of thecabozantinib after 60 minutes of testing.

Example 42F

The dosage forms prepared in Examples 42A-42D were tested for impuritiesand stability using the following HPLC method:

Parameter Setting/Description System HPLC Equipped with a UV/VisDetector Column YMC Pack ODS AQ, 4.6 × 150 mm, 3 μm, or EquivalentDetection UV at 245 nm Flow rate 0.8 mL/min Injection volume 5 μL Columntemperature 20° C. Sample temperature Ambient Run time 60 minutes Modeof Analysis Gradient as shown below: Time (min) Mobile phase A Mobilephase B 0 70 30 15 45 55 36 25 75 44 20 80 53 20 80 53.5 70 30 60 70 30

Mobile phase A was a buffer prepared by dissolving 2.72 g of Potassiumdihydrogen phosphate and 1 mL of Triethylamine in 1000 mL of water, andadjust the pH to 3.20±0.05 with phosphoric acid.

Mobile phase B was acetonitrile/methanol/water in a volume ratio of60/30/10.

The results of the testing were as follows:

RRT 0.27 0.70 0.75 0.83 0.95 1.09 1.42 1.62 Ex 42A Initial 0.07 60°C./75% 0.07 0.03 R.H. 1 week 60° C./75% 0.08 0.06 R.H. 2 week Ex 42CInitial 0.04 0.02 60° C./75% 0.04 0.02 R.H. 1 week 60° C./75% 0.04 0.02R.H. 2 week Ex 42D Initial 0.02 0.03 0.03 (CT1902211) 60° C./75% 0.020.06 0.07 R.H. 1 week 60° C./75% 0.03 0.03 0.07 R.H. 2 week Ex 42DInitial 0.03 0.03 (CT1902212) 60° C./1 week 0.03 0.03 0.06 60° C./2 week0.01 0.02 0.05

The capsules were stored in a high-density polyethylene (HDPE) bottlewith child resistant closure and foil induction seal (126 c.c, with 2˜3g of silica gel).

Employing the above HPLC method the cabozantinib monolauryl sulfatedosage forms were determined to have NMT 0.5% of any individualimpurity, preferably more than 0.35% of any individual impurity and mostpreferably not more than 0.25% of any individual impurity and the totalimpurity should not be more than 1.0%, preferably not more than 0.75%and most preferably not more than 0.60%.

Example 42G

The capsules prepared in Examples 42A (Test Formulation 1 or T1) and 42B(Test Formulation 2 or T2) containing cabozantinib monolauryl sulfate(equivalent to 20 mg of cabozantinib free base) were administered to six(6) healthy adult beagle dogs in a fasted state along with an equivalent20 mg cabozantinib malate tablet prepared in Example 42C (equivalent to20 mg of cabozantinib free base) in a single-center, single-dose study.Blood samples were drawn before dosing and at 0.25, 1, 1.5, 2, 3, 4, 6,8, 12, 16 and 24 hours after dosing. The mean cabozantinib plasma valueswere determined as follows:

Capsule Prepared Capsule Prepared Tablet Prepared According Exam-According Exam- According Exam- ple 42A (T1) ple 42B (T2) ple 42C (R)AUC_(0-t) 4022.38 3827.32 4601.27 (ng · hr/mL) C_(max) 746.83 670.10729.52 (ng/mL)

A graph of the mean plasma profiles is shown in FIG. 12.

The individual data from the study is shown in the following tables:

C_(max) (ng/mL) CV 101 102 201 202 301 302 Mean SD (%) Ex 42C (R) 615.78747.13 486.31 601.65 1181.30 744.96 729.52 242.11 33.19 Ex 42A (T1)1189.18 767.83 735.43 660.40 850.18 277.93 746.83 294.71 39.46 Ex 42B(T2) 528.99 339.47 936.48 934.88 1211.58 69.18 670.10 430.02 64.17

AUC_(0-t) (ng · hr/mL) CV 101 102 201 202 301 302 Mean SD (%) Ex 42C (R)2596.52 3067.45 5830.22 6636.12 6689.28 2788.05 4601.27 1983.44 43.11 Ex42A (T1) 4849.99 3185.92 4089.18 3816.12 6165.36 2027.73 4022.38 1414.4035.16 Ex 42B (T2) 2096.90 2992.37 5455.89 6128.48 5980.58 309.72 3827.322393.70 62.54

Tablet Prepared as in Example 42C (R) Time Blood concentration (ng/mL)(hr) 101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NANA NA 0.25 139.31 454.41 206.06 142.05 213.12 333.71 248.11 123.26 49.681 615.78 747.13 300.71 410.80 524.89 744.96 557.38 180.57 32.40 1.5561.35 552.08 382.12 490.02 725.62 669.01 563.37 123.16 21.86 2 464.79554.73 420.41 601.65 1181.30 628.17 641.84 275.97 43.00 3 416.21 414.54356.87 508.70 1074.27 407.07 529.61 271.31 51.23 4 287.92 343.52 486.31504.90 729.04 330.56 447.04 163.72 36.62 6 93.77 118.56 378.94 443.94317.94 105.42 243.09 155.67 64.04 8 57.12 66.09 313.78 378.56 226.3140.24 180.35 146.34 81.14 12 33.38 38.31 204.16 224.43 130.69 15.11107.68 92.05 85.49 16 21.67 22.13 149.77 166.24 105.63 7.47 78.82 70.6689.65 24 10.56 7.49 133.02 106.83 91.68 2.55 58.69 58.35 99.42

Capsule Prepared as in Example 42A (T1) Time Blood concentration (ng/mL)(hr) 101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NANA NA 0.25 125.80 3.98 BLQ 350.06 BLQ 1.48 120.33 163.77 136.11 1 178.09148.77 484.49 645.16 346.82 12.74 302.68 234.76 77.56 1.5 786.97 767.83531.84 477.84 816.04 32.23 568.79 298.62 52.50 2 919.53 750.95 735.43430.88 850.18 90.36 629.56 312.70 49.67 3 1189.18 546.82 546.32 660.40659.94 184.67 631.22 324.57 51.42 4 659.08 367.36 440.11 396.28 544.10277.93 447.47 135.61 30.31 6 295.87 180.11 218.28 233.47 311.46 229.06244.71 49.63 20.28 8 107.14 89.34 122.41 108.73 219.27 134.75 130.2746.21 35.47 12 50.18 48.68 83.48 64.52 151.47 58.62 76.16 38.98 51.19 1629.58 29.05 60.85 43.59 164.85 25.86 58.96 53.49 90.72 24 30.87 12.1764.91 27.06 137.78 20.39 48.86 47.16 96.51

Capsule Prepared as in Example 42B (T2) Time Blood concentration (ng/mL)(hr) 101 102 201 202 301 302 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ NANA NA 0.25 528.99 25.34 826.36 390.63 293.54 2.72 378.31 341.15 90.18 1407.28 176.00 936.48 917.10 584.82 8.04 611.61 433.54 70.89 1.5 344.09257.35 664.52 670.35 1211.58 53.73 650.05 473.12 72.78 2 239.98 292.17632.86 934.88 887.19 69.18 631.03 397.33 62.97 3 207.79 339.47 517.94700.89 633.25 59.11 477.80 289.16 60.52 4 192.16 314.90 607.70 475.12663.63 42.17 447.15 281.32 62.91 6 103.20 265.80 298.65 295.25 291.7123.62 227.31 135.82 59.75 8 71.03 168.25 167.56 312.45 190.24 11.56170.45 123.57 72.50 12 33.80 85.42 103.75 146.47 128.13 4.05 95.60 63.4966.41 16 21.72 48.07 70.41 97.84 96.96 2.05 66.82 45.01 67.37 24 11.2010.92 70.89 52.34 79.99 BLQ 67.74 14.10 20.81

Example 43

Liquid dosage forms may be prepared using the mono- or di-lauryl sulfatesalts of acalabrutinib, afatinib, alectinib, axitinib, bosutinib,brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib,dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib,gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib,nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, orvemurafenib as prepared in Examples 1, 11-14, 16-17, 21, 25-27, 33-34,36, 38 and 41 using the procedure described in Example 3, 9, 15, 18, 37and 39.

The composition of the capsule content comprises the following:

Wt % Wt % (preferred) KI lauryl sulfate 1-80 2.5-50  Carrier (preferablya wetting 1-90 10-80 agent, an emulsifying agent, a solubilizing agent,a surfactant or combinations thereof) with HLB value of less than 10Carrier (preferably a wetting 1-90 10-50 agent, an emulsifying agent, asolubilizing agent, a surfactant or combinations thereof) with HLB valueof 10 or greater Stabilizer 0-15 0.01-10  Total 100.0 100

Example 44

Solid dosage forms, such as a tablet or capsule may be prepared usingthe mono- or di-lauryl sulfate salts of acalabrutinib, afatinib,alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib,cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib,erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib,lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib,ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib,vandetanib, or vemurafenib as prepared in Examples 1, 11-14, 16-17, 21,25-27, 33-34, 36, 38 and 41 using the procedure described in Example 4,19, 22, 30, 33, and 34.

The composition of the solid dosage form will comprise the following:

Wt % Wt % (preferred) KI lauryl sulfate 1-80 10-60 Filler 5-90 20-70Disintegrant 0-25  2-15 Carrier (preferably a wetting agent, an 1-60 2-40 emulsifying agent, a solubilizing agent, a surfactant orcombinations thereof) with an HLB value of 10 or greaterGlidant/lubricant 0-15 0.5-10  Stabilizer 0-15 0.01-10  Binder 0-150.5-10  Total 100.0 100

Example 45

Semi-solid dosage forms may be prepared using the mono- or di-laurylsulfate salts of acalabrutinib, afatinib, alectinib, axitinib,bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib,dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib,gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib,nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib,ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, orvemurafenib as prepared in Examples 1, 11-14, 16-17, 21, 25-27, 33-34,36, 38 and 41 using the procedure described in Example 23 or 31.

The composition of the semi-solid dosage form will comprise thefollowing:

Wt % Wt % (preferred) KI lauryl sulfate 1-80 2.5-50 Viscosity enhancingagent 0-60 0.5-50 Carrier (preferably a wetting agent, an 1-90  10-50emulsifying agent, a solubilizing agent, a surfactant or combinationsthereof) with an HLB value of 10 or greater Carrier (preferably awetting agent, an 1-90  10-80 emulsifying agent, a solubilizing agent, asurfactant or combinations thereof) with HLB value of less than 10Stabilizer 0-15 0.01-10  Total 100.0 100

Example 46

A nilotinib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   a. Nilotinib free base (3 g) was suspended with MeOH (30V), the    mixture was stirred at less than 60° C., preferably about 55±5° C.    for about 20 minutes.-   b. Sodium lauryl sulfate (1 eq) and 1N HBr (1 eq) in 3V MeOH and 3V    Purified Water (including the Purified Water in the 1N HBr) were    combined and the resulting mixture was stirred at room temperature    for 10±5 min.-   c. Once all the solids in step (b) were dissolved, the nilotinib    suspension of step (a) was added to the sodium lauryl sulfate/HBr    solution of step (b) and the resulting mixture was stirred at less    than 60° C., preferably at 55±5° C. for 30±10 min.-   d. Once all the solids in the reaction mixture prepared in step (c)    were dissolved, the temperature was then adjusted to room    temperature and stirred for 60±10 min.-   e. After stirring, Purified Water (30V) was added to the reaction    mixture of step (d) and further stirred at room temperature for    about 30 min.-   f. The resulting off white crystals formed in step (e) were    collected by filtration, washed with Purified Water (5V), to yield    nilotinib monolauryl sulfate salt (3.747 g) (yield: 88.81%) (HPLC    purity: 99.52%).

Crystallization Method A

Crude nilotinib monolauryl sulfate salt prepared according to steps(a)-(f) was recrystallized according to the following procedure:

-   1. MeOH (15V) was added to crude nilotinib monolauryl sulfate (2 g),    the mixture stirred at a temperature less than 60° C., preferably    about 55±5° C. until the nilotinib monolauryl sulfate was dissolved    (approximately 10±5 min).-   2. Purified Water (15V) was added to the solution of step (1) and    the temperature of less than 60° C., preferably about 55±5° C. was    maintained for 30±10 min to obtain the precipitate, and then the    temperature of the reaction mass was adjusted to room temperature.-   3. The precipitate formed in step (2) was collected by filtration    and washed with Purified Water (2×2V).-   4. The precipitate collected in step (3) was dried in high vacuo to    obtain a white crystalline nilotinib monolauryl sulfate salt    (1.7846 g) (yield: 89.2%) (HPLC purity 99.89%).

The XRPD for a white crystalline nilotinib monolauryl sulfate saltprepared by a method outlined above is shown in FIG. 13. The XRPD wasobtained using Rigaku, D/MAX 2200 and employing the following testingcondition:

-   -   Cukα₁₊₂=1.54184 Å,    -   Power: 40 kV 30 mA    -   Beam size: 1.0 mm    -   Scan axis: 2Theta/theta    -   Angle: 5˜40°    -   DivH.L.Slit: 5 mm    -   RecSlit: 1.0 mm

The crystalline nilotinib monolauryl sulfate prepared by crystallizationMethod A will exhibit one or more of the following 2θ peaks: 5.6±0.2;8.5±0.2; 9.4±0.2; 13.0±0.2; 13.6±0.2; 17.1±0.2; 19.1±0.2; 20.2±0.2;21.5±0.2; 22.0±0.2; 22.8±0.2; 24.8±0.2; 25.8±0.2; 26.1±0.2 and/or26.6±0.2.

Crystallization Method B

Crude nilotinib monolauryl sulfate salt prepared according to step(a)-(f) was recrystallized according to the following procedure:

-   1. MeOH (15V) was added to crude nilotinib monolauryl sulfate (3.747    g), the mixture stirred at a temperature less than 60° C.,    preferably about 55±5° C. until the nilotinib monolauryl sulfate was    dissolved (approximately 10±5 min).-   2. The solution of step (1) was filtered hot to remove dust or other    particulate matter and washed with MeOH (5V).-   3. The obtained filtrate was heated to a temperature less than 60°    C., preferably about 55±5° C.-   4. Purified Water (30V) was added dropwise to the solution of    step (3) over a period of about 30±10 minutes while maintaining the    temperature at about 55±5° C.-   5. Once the Purified Water was added and the precipitate was formed,    the reaction mass was cooled to room temperature, then further    cooled to 0-5° C. to allow for additional precipitation.-   6. The precipitate formed in step (5) was collected by filtration    and washed with Purified Water (2×2V).-   7. The precipitate collected in step (6) was dried in high vacuo to    obtain a white crystalline nilotinib monolauryl sulfate salt    (3.4201 g) (yield: 91.3%) (HPLC purity 99.93%).

Crystallization Method C

Crude nilotinib monolauryl sulfate salt prepared according to steps(a)-(f) was recrystallized according to the following procedure:

-   1. EtOH (35V) was added to crude nilotinib monolauryl sulfate (2 g),    the mixture stirred at a temperature less than 60° C., preferably    about 55±5° C. until the nilotinib monolauryl sulfate was dissolved    (approximately 10±5 min).-   2. Purified Water (60V) was added to the solution of step (1) and    the temperature of less than 60° C., preferably about 55±5° C. is    maintained for 30±10 min to obtain the precipitate, and then the    temperature of the reaction mass was adjusted to room temperature.-   3. The precipitate formed in step (2) was collected by filtration    and washed with Purified Water (2×2V).-   4. The precipitate collected in step (3) was dried in high vacuo to    obtain a white crystalline nilotinib monolauryl sulfate salt    (1.7695 g) (yield: 88.5%) (HPLC purity 99.88%).

The XRPD pattern for a white crystalline nilotinib monolauryl sulfatesalt prepared by crystallization Method C was obtain by the procedureoutlined in crystallization Method A and is shown in FIG. 14.

The crystalline nilotinib monolauryl sulfate prepared by crystallizationMethod C will exhibit one or more of the following 2θ peaks: 5.6±0.2;8.5±0.2; 9.2±0.2; 9.4±0.2; 13.1±0.2; 13.7±0.2; 17.1±0.2; 17.8±0.2;19.1±0.2; 20.2±0.2; 21.5±0.2; 22.0±0.2; 24.9±0.2; 25.8±0.2; 26.5±0.2;27.7±0.2 and/or 29.0±0.2.

Crystallization Method D

Crude nilotinib monolauryl sulfate salt prepared according to steps(a)-(f) was recrystallized according to the following procedure:

-   1. IPA (100V) was added to crude nilotinib monolauryl sulfate (2 g),    the mixture stirred at a temperature less than 60° C., preferably    about 55±5° C. until the nilotinib monolauryl sulfate was dissolved    (approximately 10±5 min).-   2. Purified Water (265V) was added to the solution of step (1) and    the temperature of less than 60° C., preferably about 55±5° C. was    maintained for 30±10 min to obtain the precipitate, and then the    temperature of the reaction mass was adjusted to room temperature.-   3. The precipitate formed in step (2) was collected by filtration    and washed with Purified Water (2×2V).-   4. The precipitate collected in step (3) was dried in high vacuo to    obtain a white crystalline nilotinib monolauryl sulfate salt    (1.6742 g) (yield: 83.7%) (HPLC purity 99.88%).

The XRPD pattern for a white crystalline nilotinib monolauryl sulfatesalt prepared by crystallization Method D was obtain by the procedureoutlined in crystallization Method A and is shown in FIG. 15.

The crystalline nilotinib monolauryl sulfate prepared by crystallizationMethod D will exhibit one or more of the following 2θ peaks: 5.6±0.2;8.5±0.2; 9.1±0.2; 9.6±0.2; 13.1±0.2; 13.9±0.2; 16.7±0.2; 17.2±0.2;17.9±0.2; 18.4±0.2; 19.1±0.2; 19.6±0.2; 20.9±0.2; 21.3±0.2; 23.0±0.2;24.1±0.2; 24.7±0.2; 25.8±0.2; 27.7±0.2; 29.0±0.2; 30.0±0.2; 30.7±0.2;33.8±0.2; 34.6±0.2 and/or 38.7±0.2.

Example 47

A dasatinib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   a. MeOH (25V) was added to dasatinib monohydrate (6 g), the mixture    was stirred at refluxing temperature.-   b. Sodium lauryl sulfate (1 eq) and 1N HCl (1 eq) in 3V MeOH and 3V    Purified Water (including the Purified Water in the 1N HCl) were    combined and the resulting mixture was stirred at room temperature    for 10±5 min.-   c. Once all the solids in step (b) were dissolved, the sodium lauryl    sulfate/HCl solution of step (b) was added to the dasatinib mixture    of step (a) and the resulting mixture was stirred at refluxing    temperature (65-70° C.) for about 30±10 minutes then the temperature    was adjusted to room temperature for 60±10 min.-   d. The reaction mixture of step (c) was concentrated in vacuo by    rotary evaporator (T=45° C.) until dryness.-   e. The concentrated reaction mass of step (d) was extracted with    ethyl acetate (20V) and water (10V).-   f. The organic layer of step (e) was separately washed with water    (2×10V).-   g. The washed organic layer of step (f) was concentrated in vacuo by    rotary evaporator (T=45° C.).-   h. The product of step (g) was dried in high vacuo to obtain a white    crystalline dasatinib monolauryl sulfate (8.7659 g) (yield: 98.0%)    (HPLC purity: 99.61%).-   i. IPA (10V) was added to the dasatinib monolauryl sulfate of    step (h) and stirred at room temperature for 30±10 minutes.-   j. The white solid precipitate in the reaction mass of step (i) was    collected by filtration and washed with IPA (2×2V).-   k. The washed solid precipitate of step (j) was dried in high vacuo    to obtain a white crystalline dasatinib monolauryl sulfate (7.89 g)    (yield: 90.0%) (HPLC purity: 99.82%).    Crystallization Method A

Crude dasatinib monolauryl sulfate salt prepared according to steps(a)-(k) was recrystallized according to the following procedure:

-   1. MeOH (5V) was added to crude dasatinib monolauryl sulfate (3 g),    the mixture stirred at about 60° C. for approximately 10±5 min.-   2. Isopropyl Alcohol (IPA) (40 V) and Hexane (40V) was added to the    solution of step (1) while maintaining the temperature at about    60° C. until the precipitate was formed then the temperature of the    reaction mass was adjusted to room temperature.-   3. The temperature of the reaction mass of step (2) was adjusted to    0-5° C. for about 30±10 minutes and the precipitate was collected by    filtration and washed with hexane (2×2V).-   4. The precipitate collected in step (3) was dried in high vacuo to    obtain a white crystalline dasatinib monolauryl sulfate salt    (2.7186 g) (yield: 88.8%) (HPLC purity 99.94%).

An XRPD pattern was obtained by the procedure outlined in Example 46 ona sample of the dasatinib lauryl sulfate prepared by crystallizationMethod A and is shown in FIG. 16.

The crystalline dasatinib monolauryl sulfate prepared by crystallizationMethod A will exhibit one or more of the following 2θ peaks: 6.9±0.2;8.3±0.2; 9.9±0.2; 10.5±0.2; 12.6±0.2; 13.1±0.2; 14.7±0.2; 15.8±0.2;16.3±0.2; 17.1±0.2; 17.2±0.2; 17.4±0.2; 18.4±0.2; 19.4±0.2; 20.1±0.2;21.5±0.2; 22.6±0.2; 23.5±0.2; 24.4±0.2; 25.0±0.2; 26.0±0.2; 26.5±0.2;26.9±0.2; 27.4±0.2; 27.8±0.2; 28.7±0.2; 29.1±0.2; 30.4±0.2; 31.6±0.2;34.6±0.2; 37.5±0.2; and/or 39.2±0.2.

Crystallization Method B

Crude dasatinib monolauryl sulfate salt prepared according to step(a)-(k) was recrystallized according to the following procedure:

-   1. MeOH (5V) was added to crude dasatinib monolauryl sulfate (3 g),    the mixture stirred at about 60° C. for approximately 10±5 min then    the temperature was adjusted to room temperature.-   2. Ether (60 V) was added to the solution of step (1) while    maintaining the temperature at room temperature.-   3. The temperature of the reaction mass of step (2) was adjusted to    0-5° C. for about 30±10 minutes and the precipitate was collected by    filtration and washed with ether (2×2V).-   4. The precipitate collected in step (3) was dried in high vacuo to    obtain a white crystalline dasatinib monolauryl sulfate salt    (2.8910 g) (yield: 94.5%) (HPLC purity 99.85%).

An XRPD pattern was obtained by the procedure outlined in Example 46 ona sample of the dasatinib lauryl sulfate prepared by crystallizationMethod B and is shown in FIG. 17.

The crystalline dasatinib monolauryl sulfate prepared by crystallizationMethod B will exhibit one or more of the following 2θ peaks: 6.6±0.2;8.1±0.2; 9.6±0.2; 10.2±0.2; 10.7±0.2; 12.4±0.2; 12.8±0.2; 14.4±0.2;15.5±0.2; 16.0±0.2; 17.1±0.2; 18.2±0.2; 19.0±0.2; 19.8±0.2; 20.5±0.2;21.3±0.2; 22.3±0.2; 23.2±0.2; 24.1±0.2; 24.8±0.2; 25.8±0.2; 26.1±0.2;26.7±0.2; 27.2±0.2; 27.5±0.2; 28.4±0.2; 28.8±0.2; 30.8±0.2; 31.4±0.2;32.5±0.2; 33.3±0.2; 34.1±0.2; 34.4±0.2; and/or 39.5±0.2.

Example 47 A

The solubility of the crystalline dasatinib monolauryl sulfate preparedin Example 47, Method A, amorphous dasatinib monolauryl sulfate preparedin Example 12, amorphous dasatinib dilauryl sulfate prepared in Example13 and a commercially available sample of dasatinib monohydrate freebase was measured by adding the sample to 500 mL of the designatedmedium at 37° C. and shaking or stirring for at least 18 hours to obtaina saturated condition. The reaction mass was filtered and the filtratesolution was measured by HPLC. The results of the solubilitymeasurements are as follows:

Dasatinib Dasatinib Dasatinib Monolauryl Monolauryl Dasatinib DilaurylSulfate Sulfate Monohydrate Sulfate (crystal) (amorphous) pH condition(μg/mL) (μg/mL) (μg/mL) (μg/mL) 0.1N HCl, 654.4 48.9 361.9 307.9 pH =1.0 0.05M acetate 86.9 16.3 39.4 22.6 buffer, pH = 4.5 0.05M phosphate0.18 11.4 4.35 4.71 buffer, pH = 6.8

The results of the solubility study showed the aqueous solubility ofdasatinib varied with pH.

Example 48

A dasatinib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   a. MeOH (25V) was added to dasatinib monohydrate (3 g), the mixture    was stirred at refluxing temperature.-   b. Sodium lauryl sulfate (1 eq) and 1N HCl (1 eq) in 3V MeOH and 3V    Purified Water (including the Purified Water the 1N HCl) were    combined and the resulting mixture was stirred at room temperature    for 10±5 min.-   c. Once all the solids in step (b) were dissolved, the sodium lauryl    sulfate/HCl solution of step (b) was added to the dasatinib mixture    of step (a) and the resulting mixture was stirred at refluxing    temperature (65-70° C.) for about 30±10 minutes then the temperature    was adjusted to room temperature for 60±10 min.-   d. The reaction mixture of step (c) was concentrated in vacuo by    rotary evaporator (T=45° C.) until dryness.-   e. The concentrated reaction mass of step (d) was extracted with    ethyl acetate (20V) and water (10V).-   f. The organic layer of step (e) was separately washed with water    (2×10V).-   g. The washed organic layer of step (f) was concentrated in vacuo by    rotary evaporator (T=35° C.).-   h. MeOH (10V) was added to the product of step (g) and heated at    60° C. until dissolved.-   i. The solution of step (h) was filtered under hot conditions to    remove any dust or other particulate matter and washed with MeOH    (5V).-   j. The filtrate of step (i) was concentrated in vacuo by rotary    evaporator (T=45° C.) until dryness.-   k. The product of step (j) was dried in high vacuo to obtain a white    crystalline dasatinib monolauryl sulfate (4.419 g) (yield: 98.8%)    (HPLC purity: 99.66%).    Crystallization Method C

Crude dasatinib monolauryl sulfate salt prepared according to steps(a)-(k) was recrystallized according to the following procedure:

-   1. MeOH (5V) was added to crude dasatinib monolauryl sulfate (3 g)    and the mixture stirred at about 60° C. for approximately 10±5 min.-   2. IPA (5V) and Hexane (25V) were added to the solution of step (1)    while maintaining the temperature at about 60° C. until the    precipitate was formed then the temperature of the reaction mass was    adjusted to room temperature.-   3. The temperature of the reaction mass of step (2) was adjusted to    0-5° C. for about 30±10 minutes and the precipitate was collected by    filtration and washed with hexane (2×2V).-   4. The precipitate collected in step (3) was dried in high vacuo to    obtain a white crystalline dasatinib monolauryl sulfate salt    (2.81 g) (yield: 93.7%) (HPLC purity 99.90%).-   5. Steps 1-4 were repeated to obtain a white crystalline dasatinib    monolauryl sulfate salt (2.68 g) (yield: 95.4%) (HPLC purity    99.96%).

An XRPD pattern was obtained by the procedure outlined in Example 46 ona sample of the dasatinib lauryl sulfate prepared by crystallizationMethod C and is shown in FIG. 18.

The crystalline dasatinib monolauryl sulfate prepared by crystallizationMethod C will exhibit one or more of the following 2θ peaks: 5.9±0.2;6.5±0.2; 7.9±0.2; 9.5±0.2; 10.2±0.2; 12.3±0.2; 12.7±0.2; 14.4±0.2;14.9±0.2; 16.0±0.2; 16.8±0.2; 17.1±0.2; 18.1±0.2; 19.1±0.2; 19.8±0.2;21.1±0.2; 22.2±0.2; 23.2±0.2; 24.1±0.2; 24.7±0.2; 25.6±0.2; 26.6±0.2;27.6±0.2; 28.1±0.2; 28.5±0.2; 28.9±0.2; 30.0±0.2; 30.8±0.2; 31.3±0.2;34.2±0.2; 35.4±0.2; 37.2±0.2 and/or 38.9±0.2.

Crystallization Method D

A crude dasatinib monolauryl sulfate salt was prepared according to step(a)-(k) wherein the process produced a crude white crystalline dasatinibmonolauryl sulfate (4.4373 g) (yield: 99.2%) (HPLC purity: 99.58%) whichwas recrystallized according to the following procedure:

-   1. IPA (6V) was added to crude dasatinib monolauryl sulfate (3 g)    and the mixture was stirred at room temperature for about 30±10    minutes.-   2. The precipitated white solid was filtered and washed with IPA    (2V).-   3. The precipitate collected in step (2) was dried in high vacuo to    obtain a white crystalline dasatinib monolauryl sulfate salt    (2.83 g) (yield: 94.3%) (HPLC purity 99.75%).-   4. Steps 1-3 were repeated to obtain a white crystalline dasatinib    monolauryl sulfate salt (2.70 g) (yield: 95.4%) (HPLC purity    99.81%).

An XRPD pattern was obtained by the procedure outlined in Example 46 ona sample of the dasatinib lauryl sulfate prepared by crystallizationMethod D and is shown in FIG. 19.

The crystalline dasatinib monolauryl sulfate prepared by crystallizationMethod D will exhibit one or more of the following 2θ peaks: 6.6±0.2;8.0±0.2; 9.5±0.2; 10.2±0.2; 10.6±0.2; 12.3±0.2; 12.8±0.2; 13.2±0.2;14.4±0.2; 15.5±0.2; 16.0±0.2; 17.1±0.2; 18.1±0.2; 18.9±0.2; 19.7±0.2;21.2±0.2; 22.2±0.2; 23.1±0.2; 24.0±0.2; 24.7±0.2; 25.7±0.2; 26.6±0.2;27.1±0.2; 28.4±0.2; 28.7±0.2; 30.9±0.2; 31.3±0.2; 32.4±0.2; 37.2±0.2;and/or 39.2±0.2.

Example 48 A

A dasatinib monolauryl sulfate salt was prepared by the followinggeneral procedure:

-   a. MeOH (25V, 1980 g) was added to dasatinib monohydrate (1 eq., 100    g), the mixture was stirred at refluxing temperature (60° C.±5° C.).-   b. Sodium lauryl sulfate (1 eq, 57 g) and 1N HCl (1 eq, 197 ml) in    MeOH (3V, 237 g) and Purified Water (1.03 V, 103 g) were combined    and the resulting mixture was stirred at room temperature for 10±5    min.-   c. Once all the solids in step (b) were dissolved, the sodium lauryl    sulfate/HCl solution of step (b) was added to the dasatinib mixture    of step (a) and the resulting mixture was stirred at refluxing    temperature (60° C.±5° C.) for about 30±10 minutes then the    temperature was adjusted to room temperature for 60±10 min.-   d. The reaction mixture of step (c) was concentrated in vacuo by    rotary evaporator (T=40° C.) until dryness.-   e. The concentrated reaction mass of step (d) was extracted with    ethyl acetate (20V, 1804 g) and stirred at room temperature for 10±5    minutes.-   f. The organic layer of step (e) was separately washed with water    (3×10V, 3×1000 g).-   g. The washed organic layer of step (f) was concentrated in vacuo by    rotary evaporator (T=35° C.) until dryness.-   h. MeOH (5V, 589 g) was added to the product of step (g) and heated    at 60° C. until dissolved.-   i. The filtrate of step (h) was concentrated in vacuo by rotary    evaporator (T=45° C.) until dryness to obtain crude dasatinib    monolauryl sulfate salt.    Crystallization Method E

Crude dasatinib monolauryl sulfate salt prepared according to steps(a)-(i) was recrystallized according to the following procedure:

-   -   1. MeOH (3V, 353 g) was added to crude dasatinib monolauryl        sulfate salt, and the mixture was stirred at 60° C.±5° C. for        10±5 min.    -   2. Add IPA (2V, 234 g) slowly to methanol solution of crude        product, and the mixture was stirred at 60° C.±5° C. for 10±5        min.    -   3. Add Hexane (40V, 4000 g) slowly to crude product to obtain        the precipitate of pure product at 45° C.±5° C. for 10±5 min        (during addition time: 30±10 min), and then adjusted to room        temperature for 30±5 min.    -   4. The temperature of the reaction mass of step (3) was adjusted        to 0-5° C. for about 30±10 min and the precipitate was collected        by filtration and washed with Hexane (2×2V, 2×200 g).    -   5. The precipitate collected in step (4) was dried in high vacuo        to obtain white crystalline of dasatinib monolauryl sulfate salt        (Yield: 79.5%, 118.5 g) (HPLC purity: 100.00%, pH Value: 4.38).

An XRPD pattern was obtained by the procedure outlined in Example 46 ona sample of the dasatinib lauryl sulfate prepared by crystallizationMethod E and is shown in FIG. 20.

The crystalline dasatinib monolauryl sulfate prepared by crystallizationMethod E will exhibit one or more of the following 2θ peaks: 6.3±0.2;9.5±0.2; 10.1±0.2; 12.2±0.2; 12.7±0.2; 14.4±0.2; 15.9±0.2; 16.7±0.2;17.0±0.2; 18.0±0.2; 19.0±0.2; 21.0±0.2; 22.2±0.2; 23.1±0.2; 23.9±0.2;24.6±0.2; 25.6±0.2; 27.5±0.2; 28.5±0.2; 28.7±0.2; 31.2±0.2; 34.2±0.2;37.2±0.2; and/or 38.7±0.2.

Example 49

A dasatinib monolauryl sulfate capsule dosage form was prepared by wetgranulating 2,982 mg of dasatinib monolauryl sulfate prepared accordingto the procedure of Example 12 with 1,500 mg of poloxamer 407(Kolliphor® P407) and 1,200 mg of poloxamer 188 (Kolliphor® P188) in3,200 mg of alcohol (95%) into a suitable container for at least 2minutes.

1,800 mg of anhydrous lactose (SuperTab® 21AN, anhydrous), 2,958 mg ofmicrocrystalline cellulose (Comprecel® M102D+), 600 mg of sodium starchglycolate (Part I) and 120 mg of colloidal silicon dioxide (AD101) (PartI) were passed through a 40 mesh screen and added to the dasatinibmonolauryl sulfate granules and mixed. The resulting blend was dried inan oven at 50° C. to evaporate the alcohol.

600 mg of sodium starch glycolate (Part II) and 120 mg of colloidalsilicon dioxide (AD101) (Part II) were passed through a 40 mesh screen,added to the dried blend containing the dasatinib monolauryl sulfategranules and mixed well. After mixing, the resulting mixture was passedthrough 40 mesh screen and collected in a suitable container. 120 mg ofmagnesium stearate was passed through a 40 mesh screen and added to thecontainer and blended with dasatinib monolauryl sulfate mixture toobtain a final blend. The final blend was filled into size 2 hardgelatin capsule.

The composition of the capsule was as follows:

mg wt % Dasatinib monolauryl sulfate 29.82 24.85 Poloxamer 407 15.0012.50 Poloxamer 188 12.00 10.00 Anhydrous lactose 18.00 15.00Microcrystalline cellulose 29.58 24.65 Sodium starch glycolate (part I)6.00 5.00 Colloidal silicon dioxide (part I) 1.20 1.00 Sodium starchglycolate (part II) 6.00 5.00 Colloidal silicon dioxide (part II) 1.201.00 Magnesium stearate 1.20 1.00 Total 120.00 100.00 Alcohol (95%)evaporated 32.00 N/A

Example 50

The capsules prepared in Example 49 containing dasatinib monolaurylsulfate were administered to nine (9) healthy subjects under fasted, fedand fasted with omeprazole pretreatment conditions. Omeprazole is acommercially available proton pump inhibitor (PPI). This was a two-partstudy. Part 1 is a single dose, open-label, randomized, 3-treatment,3-sequence, 3-period crossover bioavailability study in healthy subjectsunder fasted and fed conditions. All subjects were randomized to thesequences as shown in the following table with a 7-day washout periodbetween the periods. Part 2 is a sequential, 2-treatment, drug-druginteraction study in healthy subjects. All subjects were orallyadministered omeprazole 40 mg QD for 5 days to reach steady state and a20 mg dasatinib capsule was orally administered approximately 22 hoursafter the last dose of omeprazole. The Reference drug (Ref) wasSprycel®, dasatinib monohydrate, with a strength of 50 mg while the Testdrug (Test) was a capsule prepared according to the procedure of Example49 but containing approximately a dose of dasatinib monolauryl sulfateequivalent to 20 mg of dasatinib monohydrate. The nine (9) healthysubjects enrolled in this study were randomized to one of the sequencesas shown in the following table.

Part 1 Part 2 Se- Period Period Period Period Period quence I II III IVV 1 R T_(fast) T_(fed) Omeprazole 40 mg T_(fast) QD for 5 days 2 T_(fed)R T_(fast) Omeprazole 40 mg T_(fast) QD for 5 days 3 T_(fast) T_(fed) ROmeprazole 40 mg T_(fast) QD for 5 days

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hoursafter dosing. AUC₀₋₂₄, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults of the study were normalized to 50 mg dose and summarized in thefollowing Table:

The Pharmacokinetic Parameters for Reference and Test Formulations(Normalized to 50 mg dose) Normalized to 50 mg dose Treatment ParametersMean Ref_(Fasted) C_(max) (ng/mL) 75.5 AUC₀₋₂₄ (ng · h/mL) 282 AUC_(0-∞)(ng · h/mL) 289 Test_(Fasted) C_(max) (ng/mL) 47.0 AUC₀₋₂₄ (ng · h/mL)173.5 AUC_(0-∞) (ng · h/mL) 178.3 Test_(Fed) C_(max) (ng/mL) 28.3AUC₀₋₂₄ (ng · h/mL) 181.0 AUC_(0-∞) (ng · h/mL) 190.3 Test_(Fasted)(PPI) C_(max) (ng/mL) 57.3 with 40 mg AUC₀₋₂₄ (ng · h/mL) 176.0omeprazole AUC_(0-∞) (ng · h/mL) 181.3 Ref_(Fasted): Sprycel ® Tab 50 mgunder fasted condition Test_(Fasted): Test drug (Test) 20 mg (dasatinibmonohydrate) under fasted condition Test_(Fed): Test drug (Test) 20 mg(dasatinib monohydrate) under fed condition Test_(Fasted) (PPI) with 40mg omeprazole: Test drug (Test) 20 mg (dasatinib monohydrate) with 40 mgomeprazole under fasted condition

Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following Table:

The Comparisons between Test_(Fasted) vs. Reference_(Fasted), Test_(Fed)vs. Test_(Fasted) and Test_(Fasted) (PPI) vs. Test_(Fasted) (Normalizedto 50 mg dose) Comparisons Parameters Geometric Mean Ratios Test~RefC_(max) 100.88% (Fasted) (ng/mL) AUC₀₋₂₄ 87.63% (ng · h/mL) AUC_(0-∞)86.20% (ng · h/mL) Test_(Fed)~Test_(Fasted) C_(max) 59.80% (ng/mL)AUC₀₋₂₄ 105.37% (ng · h/mL) AUC_(0-∞) 107.51% (ng · h/mL) Test_(Fasted)C_(max) 104.23% (PPI)~Test_(Fasted) (ng/mL) AUC₀₋₂₄ 101.14% (ng · h/mL)AUC_(0-∞) 101.46% (ng · h/mL)

The data shows that the compositions of the present invention exhibit anincrease of C_(max) by 1.01 fold and a decrease of AUC by 0.88 foldcompared to the U.S. FDA approved dasatinib monohydrate. The data alsoshows that the compositions of the present invention do not exhibit agastric acid reducing agent or PPI effect i.e., the compositions of thepresent invention exhibit comparable pharmacokinetics under fasted andfasted with omeprazole co-administration.

The individual subject data normalized to 50 mg dose obtained from thestudy is as follows:

Reference Drug (Sprycel ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 BLQ BLQ BLQBLQ BLQ BLQ BLQ BLQ BLQ N/A N/A N/A 0.33 3.41 9.29 9.07 0.208 6.28 1.288.25 0.804 1.29 4.43 3.79 85.5 0.67 77.9 85 35.7 4.46 63 10.5 41.4 1.4422.3 38 31.4 82.8 1 56.3 181 28.8 18.3 57 15.6 47.3 1.56 70 52.9 53.1100.5 1.5 30.6 175 22.1 50.8 59.1 21.4 83.2 1.51 64.4 56.5 51.2 90.7 222 116 23.7 63.5 59.1 29.5 58.1 1.41 41.3 46.1 33.3 72.3 2.5 19.7 78.823.3 53.4 41.8 23.9 44.4 1.26 27.5 34.9 22.6 64.7 3 16 62.4 20.7 46.5 3516 34.9 1.05 21.2 28.2 18.5 65.6 4 12.1 43.8 29.4 34.2 24.9 11.4 30.71.26 15.5 22.6 13.4 59.5 6 7.26 27.9 13.9 22.6 13.8 12.7 21.5 0.73 6.914.1 8.64 61.1 8 4.14 17.7 10.3 12 8.51 5.86 13.4 0.56 4.49 8.55 5.3562.6 12 2.25 7.49 4.29 6.74 4.51 2.3 7.31 0.364 1.7 4.11 2.63 64.1 240.774 1.3 1.21 1.11 0.833 0.491 1.54 0.185 0.44 0.876 0.449 51.3

Test Drug under fasted condition (Concentration (ng/mL)) Time Subject(hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQBLQ N/A N/A N/A 0.33 0.43 6.85 BLQ 7.7 0.2875 BLQ 0.58 16.05 BLQ 3.545.61 158.2 0.67 2.85 55.5 12.475 71 5.925 BLQ 4.875 26.75 2.575 20.2225.95 128.4 1 4.875 74 52.25 61.25 35.75 BLQ 12.45 20.95 26.25 31.9825.84 80.8 1.5 8.95 57 33.75 40 38.5 5.475 26.5 12.5 24.475 27.46 16.7761.1 2 62.25 34.5 23.275 29.25 37.5 18.8 38 9.275 17.05 29.99 15.61 522.5 48.5 28.75 18.75 22.225 32 28.5 36.25 7.3 13.25 26.17 12.45 47.6 336.5 24.65 16.05 17.85 26 33.25 28.5 6.3 10.725 22.20 10.17 45.8 422.025 20.6 13.775 15.7 21.4 18.725 20.15 4.725 8.05 16.13 6.19 38.4 616.425 10.925 8.925 9.625 11.8 11.9 18.325 2.7 4.7 10.59 4.97 46.9 8 9.97.325 5.525 6.175 7.95 6.45 10.825 2.045 2.825 6.56 2.90 44.3 12 4.153.15 2.41 3.125 4.075 3.05 5.525 1.0125 1.195 3.08 1.43 46.5 24 1.0750.65 0.45 0.6825 1.065 0.445 1.0975 0.35 0.365 0.69 0.32 45.9

Test Drug under fed condition (Concentration (ng/mL)) Time Subject (hr)1 2 3 4 5 6 7 8 9 Mean SD CV % 0 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ N/AN/A N/A 0.33 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ N/A N/A N/A 0.67 0.635BLQ 0.6125 BLQ BLQ BLQ BLQ BLQ BLQ 0.14 0.28 198.5 1 2.0625 BLQ 0.755BLQ BLQ 1.2025 1.47 0.95 0.4775 0.77 0.73 94.8 1.5 5.05 0.5025 1.285 BLQ3.2 8.55 4.925 3.725 2.75 3.33 2.66 79.8 2 10.9 2.005 3.875 BLQ 3515.925 5.275 12.225 7.825 10.34 10.57 102.2 2.5 16 6.875 5.475 0.7 5120.5 9.65 14.15 15.325 15.52 14.64 94.4 3 21.775 27.75 7.475 2.092538.25 25.5 12.175 16.175 21.7 19.21 11.05 57.5 4 38.25 43.5 13.35 8.933.25 24.125 19.625 15.375 17.8 23.80 11.95 50.2 6 27.75 24.45 17.8521.225 21.625 10.9 19.85 6.3 8.65 17.62 7.39 41.9 8 16.075 16.7 9.2512.55 13.25 6.25 15.625 4.45 5.825 11.11 4.77 43 12 6.35 6.5 4.675 4.8257.5 3.375 6.75 2.3375 2.3925 4.97 1.94 39 24 1.8575 2.2725 0.9075 1.15251.5725 0.94 1.59 0.55 0.475 1.26 0.61 48.3

Test Drug under fasted condition with 40 mg omeprazole (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 BLQ BLQ BLQBLQ BLQ BLQ BLQ BLQ BLQ N/A N/A N/A 0.33 BLQ BLQ BLQ BLQ BLQ 1.3325 BLQBLQ BLQ 0.15 0.45 300 0.67 3.975 18.525 3.525 BLQ BLQ 40.75 9.825 1.9350.3725 8.77 13.42 153.1 1 109 120.75 39.75 0.3125 0.2525 44.25 16.1252.4725 3.7 37.40 47.02 125.7 1.5 63.5 75.75 101.25 2.775 3.475 38 18.4254.75 41.25 38.80 35.36 91.1 2 37.5 45.75 66 9.1 13.1 21.2 15.175 17.12528.75 28.19 18.57 65.9 2.5 30.25 37 46.5 25.25 26.25 16.775 14.075 2818.525 26.96 10.24 38 3 26 24.6 40.75 19.675 26.75 12.875 13.05 27.7513.05 22.72 9.18 40.4 4 17.325 22.825 33 17.575 15.65 10.1 10.875 20.77511.225 17.71 7.25 40.9 6 7.75 14.85 19.825 11.725 11.55 5.65 12.1 9.5254.55 10.84 4.71 43.5 8 5.225 8.55 12.55 6.625 7.325 2.85 7.575 6.05 2.86.62 2.99 45.1 12 2.2725 3.625 5.15 2.49 2.9 1.465 3.6 2.4475 1.43252.82 1.17 41.6 24 0.6775 0.785 0.925 0.7525 1.11 BLQ 0.86 0.46 0.28250.65 0.35 53.1

A graph of the normalized mean plasma profiles provided in Example 50 isshown in FIG. 21.

Example 51

A dasatinib monolauryl sulfate capsule dosage form was prepared bymixing 7730 mg of dasatinib monolauryl sulfate prepared according to theprocedure of Example 48 A, crystallization Method E, which had beenpassed through a 60 mesh sieve with 2500 mg of anhydrous lactose, 6770mg of microcrystalline cellulose, 3000 mg of poloxamer 407, 2500 mg ofpoloxamer 188, 750 mg of hydroxypropyl cellulose (HPC-H), 500 mg ofsodium starch glycolate (part I) and 250 mg of colloidal silicon dioxide(part I) which had been passed through a 40 mesh screen for 2 minutes.

The resulting mixture was wet granulated with 2500 mg of an alcoholsolution prepared by mixing alcohol (95%) and purified water at a weightratio of 1:1. The resulting granules were dried in an oven at 50° C. toevaporate the alcohol and water.

The dry granules were passed through a 40 mesh sieve and mixed 500 mg ofsodium starch glycolate (part II) and 250 mg of colloidal silicondioxide (part II) which had been passed through a 40 mesh sieve. 250 mgof magnesium stearate which had been passed through a 40 mesh sieve wasadded to the resulting mixture and blended to obtain a final blend. Thefinal blend was filled into size 1 hard gelatin capsule.

The composition of the capsule was as follows:

mg wt % Dasatinib monolauryl sulfate (DSB-1LS) 77.30 30.92 Poloxamer 40730.00 12.00 Poloxamer 188 25.00 10.00 Hydroxypropyl cellulose (HPC-H)7.50 3.00 Anhydrous lactose 25.00 10.00 Microcrystalline cellulose 67.7027.08 Sodium starch glycolate (part I) 5.00 2.00 Colloidal silicondioxide (part I) 2.50 1.00 Sodium starch glycolate (part II) 5.00 2.00Colloidal silicon dioxide (part II) 2.50 1.00 Magnesium stearate 2.501.00 Total 250.00 100.00 Alcohol (95%) 12.50 N/A Purified water 12.50N/A

Example 51 A

The capsules prepared in Example 51 containing dasatinib monolaurylsulfate were administered to healthy subjects under fasted, fed andfasted with omeprazole pretreatment conditions. Omeprazole is acommercially available proton pump inhibitor (PPI). This was a two-partstudy. Part 1 was a single dose, open-label, randomized, 4-treatment,4-sequence, 4-period crossover bioavailability study in ten (10) healthysubjects under fasted and fed conditions. All subjects were randomizedto the sequences as shown in the following table with a 3-day or 4-daywashout period between the periods. Part 2 is a sequential, 2-treatment,drug-drug interaction study in nine (9) healthy subjects. All subjectswere orally administered omeprazole 40 mg QD for 5 days to reach steadystate and a 50 mg dasatinib capsule was orally administeredapproximately 22 hours after the last dose of omeprazole. The Referencedrug (Ref) was Sprycel®, dasatinib monohydrate, with a strength of 50 mg(free base) while the Test drug (Test) was a capsule prepared accordingto the procedure of Example 51 but containing approximately 50 mg ofdasatinib (free base). The ten (10) healthy subjects for part 1 or nine(9) healthy subjects for part 2 enrolled in this study were randomizedto one of the sequences as shown in the following table.

Part 1 Sequence Period I Period II Period III Period IV 1 Rfast TfastTfed Rfed 2 Tfed Rfast Rfed Tfast 3 Rfed Tfed Tfast Rfast 4 Tfast RfedRfast Tfed Part 2 Sequence Period I Period II Period III 1 TfastOmeprazole 40 mg QD Tfast for 5 days * Rfast: Reference under fastedcondition; Rfed: Reference under fed condition; Tfast Test under fastedcondition; Tfed: Test under fed condition. * Tfast Test under fastedcondition

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hoursafter dosing. AUC₀₋₂₄, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults were summarized in the following table:

The Pharmacokinetic Parameters for Reference and Test Formulations 50 mgdose Treatment Parameters Mean Part 1 Ref_(Fasted) C_(max) (ng/mL) 97.8AUC₀₋₂₄ (ng · h/mL) 302 AUC_(0-∞) (ng · h/mL) 307 Ref_(Fed) C_(max)(ng/mL) 47.2 AUC₀₋₂₄ (ng · h/mL) 235 AUC_(0-∞) (ng · h/mL) 244Test_(Fasted) C_(max) (ng/mL) 73.6 AUC₀₋₂₄ (ng · h/mL) 255 AUC_(0-∞) (ng· h/mL) 261 Test_(Fed) C_(max) (ng/mL) 35.9 AUC₀₋₂₄ (ng · h/mL) 224AUC_(0-∞) (ng · h/mL) 235 Part 2 Test_(Fasted) C_(max) (ng/mL) 82.7AUC₀₋₂₄ (ng · h/mL) 297 AUC_(0-∞) (ng · h/mL) 303 Test_(Fasted) (PPI)C_(max) (ng/mL) 98.6 with 40 mg AUC₀₋₂₄ (ng · h/mL) 349 omeprazoleAUC_(0-∞) (ng · h/mL) 356 * Ref_(Fasted): Sprycel ® Tab 50 mg underfasted condition * Ref_(Fed): Sprycel ® Tab 50 mg under fed condition *Test_(Fasted): Test drug (Test) 50 mg under fasted condition *Test_(Fed): Test drug (Test) 50 mg under fed condition * Test_(Fasted)(PPI) with 40 mg omeprazole: Test drug (Test) 50 mg with 40 mgomeprazole under fasted condition

Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following table:

The Comparisons between Test_(Fasted) vs. Reference_(Fasted), Test_(Fed)vs. Reference_(Fed), Test_(Fasted) vs. Test_(Fed) and Test_(Fasted)(PPI) vs. Test_(Fasted) Comparisons Parameters Geometric Mean RatiosTest~Ref C_(max) 78.96% (Fasted) (ng/mL) AUC₀₋₂₄ 84.07% (ng · h/mL)AUC_(0-∞) 84.69% (ng · h/mL) Test~Ref C_(max) 75.90% (Fed) (ng/mL)AUC₀₋₂₄ 97.71% (ng · h/mL) AUC_(0-∞) 98.24% (ng · h/mL)Test_(Fast)~Test_(Fed) C_(max) 191.81% (ng/mL) AUC₀₋₂₄ 108.97% (ng ·h/mL) AUC_(0-∞) 106.71% (ng · h/mL) Test_(Fasted) C_(max) 117.44%(PPI)~Test_(Fasted) (ng/mL) AUC₀₋₂₄ 113.15% (ng · h/mL) AUC_(0-∞)113.13% (ng · h/mL)

The data shows that the compositions of the present invention exhibit adecrease of C_(max) by 0.79 fold and a decrease of AUC by 0.84 foldcompared to the U.S. FDA approved dasatinib monohydrate under fastedcondition. The data shows that the compositions of the present inventionexhibit a decrease of C_(max) by 0.76 fold and a decrease of AUC by 0.98fold compared to the U.S. FDA approved dasatinib monohydrate under fedcondition. The data also shows that the compositions of the presentinvention exhibit a positive gastric acid reducing agent or PPI effecti.e., the compositions of the present invention during fastedco-administration with omeprazole exhibited an increase of C_(max) by1.17 fold and an increase of AUC by 1.13 fold compared to the fastedcondition.

A graph of the mean plasma profiles under fasted condition for thisExample is shown in FIG. 22 A.

A graph of the mean plasma profiles under fed condition for this Exampleis shown in FIG. 22 B.

A graph of the mean plasma profiles with 40 mg omeprazole under fastedcondition for this Example is shown in FIG. 22C.

The individual subject data of 50 mg dose obtained from the study is asfollows:

Part 1: Reference Drug (Sprycel ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 10 Mean SD CV % 0 0 0 0 0 00 0 0 0 0 0 0 — 0.33 26.1 8.34 43 2.9 12.4 2.79 123 32.8 1.97 22.9 27.636.3 131.5 0.67 184 131 55.6 23.2 71.1 51 121 26.4 39.5 153 85.6 57.166.8 1 194 167 36.6 49 60 69.3 76.7 16.1 31.3 128 82.8 60.2 72.7 1.5 11684.8 22.3 65.5 41.5 71 49.6 13.5 21.5 80.9 56.7 32.9 58.1 2 81.3 52.816.4 60.3 31.7 76.2 37.6 9.74 15.9 59.2 44.1 25.6 58.1 2.5 58.9 36.5 1547.5 24.6 60.4 29.1 12.2 18.4 55.2 35.8 18.6 52 3 49.4 28.5 14.2 38.824.4 59.3 25.2 15.4 20.2 45.7 32.1 15.4 47.9 4 39 21.4 12.1 24.5 30.936.1 24 9.45 20.1 39.4 25.7 10.6 41.1 6 19.1 12.7 9.37 11.7 16.7 16.621.7 7.8 16.7 20.3 15.3 4.68 30.7 8 13.5 8.27 6.45 7.51 11.2 11.8 115.48 9.4 12.9 9.75 2.75 28.3 12 5.52 4.34 2.67 3.96 4.79 5.13 4.54 2.064.8 5.19 4.3 1.12 26.1 24 1.13 0.669 0.523 0.679 0.631 1.15 0.911 0.3080.684 1.11 0.78 0.284 36.5

Part 1: Test Drug (Example 51) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 10 Mean SD CV % 0 0 0 0 0 00 0 0 0 0 0 0 — 0.33 10.2 48.6 0.121 0 4.8 2.33 47.4 37.2 3.81 20.4 17.519.7 112.7 0.67 67.6 74.7 2.32 5.16 64.1 76.3 105 31.4 42.4 77 54.6 33.461.2 1 110 51.9 10.4 15.5 52.1 130 74.3 21.6 42.5 97.5 60.6 41.3 68.21.5 91.3 41.8 16.8 33.2 33.5 91.1 42.9 15.8 27 63.2 45.7 27.6 60.4 261.2 39.2 10.8 45.2 27.6 67.7 32.1 12.3 22.3 43.1 36.2 19 52.6 2.5 51.336.3 9.33 26.6 21.7 51.5 26.5 10.6 18 36.6 28.8 15 52 3 43.5 30.5 7.7417.7 18.6 41.7 21.7 8.64 18 38.2 24.6 13.1 53.2 4 30.3 20.3 6.53 13 22.430.8 19.6 6.12 14.2 29.3 19.3 9.23 47.9 6 14.6 12.3 29.3 9.69 19.1 18.421.8 3.72 10.4 18.4 15.8 7.22 45.8 8 9.76 7.97 14.6 6.11 14.5 12.3 11.92.65 4.92 13.4 9.81 4.22 43.1 12 5.03 3.96 6.09 3.02 6.74 6.11 4.97 1.032.49 6.21 4.57 1.89 41.4 24 0.989 0.743 1.2 0.63 1.18 1.29 0.858 0.2240.479 1.41 0.9 0.383 42.6

Part 1: Reference Drug (Sprycel ®) under fed condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 10 Mean SD CV % 0 0 0 0 0 00 0 0 0 0 0 0 — 0.33 7.74 0.773 5.61 1.04 1.01 1.24 3.45 0 0 0 2.09 2.67127.8 0.67 35.3 4.93 45.1 10.9 10.9 5.11 31.3 3.97 0.54 1.33 14.9 16.1107.8 1 53.7 14.4 55.2 25.8 19.9 6.78 38.1 27.5 2.57 14.6 25.9 18.2 70.51.5 53 47.3 29.6 36.4 36.8 11.3 31.1 26.2 13.7 69.7 35.5 17.7 49.8 2 4560.2 21.4 34.4 47.2 24.3 31.4 17.9 27.4 76 38.5 18.6 48.2 2.5 41.9 15.917.2 37.3 37.9 37.5 23.8 16.1 25.1 44.3 29.7 11.2 37.8 3 34.6 39.2 15.538.1 39.2 49 20.5 10.1 23.5 39.1 30.9 12.6 40.8 4 24.5 31.4 12.2 26 2946.2 17.9 7.04 13.8 32.1 24 11.6 48.3 6 14.7 23.1 8.43 12.8 19.7 29.111.7 4.48 12.9 18.8 15.6 7.24 46.5 8 10.6 14.7 6.29 7.01 13.9 16.1 9.072.72 7 12.5 9.99 4.3 43.1 12 5.65 6.8 3.78 3.03 5.45 8.14 5.57 1.22 2.835.68 4.82 2.07 43 24 2.3 1.41 1.09 0.585 1.12 1.68 1.09 0.475 0.807 2.141.27 0.615 48.5

Part 1: Test Drug (Example 51) under fed condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 10 Mean SD CV % 0 0 0 0 0 00 0 0 0 0 0 0 — 0.33 0 0 0 0 0.307 0.44 0 0.218 0 0.105 0.107 0.161 1500.67 0.572 0 0 0.8 4.04 3.63 0.228 1.16 0 0 1.04 1.53 146.4 1 1.66 00.17 1.65 6.88 5.67 0.731 1.81 0.497 0.127 1.92 2.41 125.5 1.5 6.23 00.629 9.78 9.82 7.68 2.52 12.4 3.29 1.08 5.34 4.43 83 2 18.4 0.336 1.6821.7 16.8 9.79 4.89 22.1 9.64 4.42 11 8.24 75 2.5 34.4 3.4 3.26 26.425.8 15.9 8.83 20.1 30 22.9 19.1 11 57.3 3 38.8 10.2 7.19 28.6 48 4516.8 18.1 58.7 33.8 30.5 17.3 56.7 4 39.7 25.9 24.9 24.7 31 47.4 29.811.7 38.6 30.9 30.5 9.87 32.4 6 33.8 25.2 17.4 16.8 20.1 32.3 23.4 6.8217.4 18.2 21.1 7.94 37.6 8 18.1 14.2 16.1 10.3 15 16.6 15.6 3.23 9.3511.1 13 4.48 34.6 12 8.05 6.02 9.45 5.62 5.69 7.16 6.98 1.21 3.59 5.295.91 2.31 39 24 2.86 1.41 1.86 1.07 0.972 1.52 1.59 0.259 0.6 1.95 1.410.74 52.5

Part 2: Test Drug (Example 51) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 0 0 0 0 0 00 0 0 0 0 — 0.33 16.7 15.5 0 52.3 28.7 2.05 31.6 0.309 70.2 24.2 24.4101 0.67 82.9 89.4 0 89 42.5 46.6 70.7 22.6 69.8 57.1 31.3 54.9 1 74.784.7 0.725 113 39.7 145 52.6 48.7 54.3 68.2 42.4 62.3 1.5 52.2 46.3 6.1384.8 30.5 103 36.1 85.4 47.1 54.6 30.8 56.5 2 41.7 40.4 6.31 63.6 26.278.4 26.9 54.5 39.8 42 21.5 51.3 2.5 34.8 31.9 6.85 44.1 22.3 60.1 20 3932.1 32.4 15.3 47.2 3 32 37.4 15.4 30.6 22.7 51 17.7 30.6 27.5 29.4 10.736.5 4 25.3 29.5 45.1 24.6 17.9 40.7 15.5 22.8 21.9 27 9.93 36.7 6 24.713.5 35.2 13.3 11 25.2 11.5 15.4 12.1 18 8.42 46.8 8 14.9 8.3 21.1 7.986.47 17.8 6.99 8.49 8.05 11.1 5.38 48.4 12 6.65 4.23 7.29 5.1 2.03 7.632.89 4.21 4.06 4.9 1.94 39.6 24 1.66 0.756 1.44 0.655 0.335 1.39 0.5740.714 0.864 0.932 0.453 48.6

Part 2: Test Drug (Example 51) under fasted condition with 40 mgomeprazole (Concentration (ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9Mean SD CV % 0 0 0 0 0 0 0 0 0 0 0 0 — 0.33 1.36 9.01 3.08 21.6 13.83.69 3.3 1.95 3.37 6.8 6.83 100.6 0.67 6.29 68 31.5 98.9 40.9 148 37.651.2 17.8 55.6 44.1 79.4 1 6.41 125 82.7 102 67.5 180 31.6 72.7 84.583.6 50.5 60.4 1.5 51.3 62 70.5 75.7 56.7 124 27.4 81.1 80.5 69.9 26.437.8 2 127 41.6 46.5 51.5 49.4 90.6 19.3 46.7 52.5 58.3 31.6 54.2 2.5107 28.6 34.4 41.5 39.2 71.8 17.4 35.7 45 46.7 27 57.7 3 70.2 22.6 32.231.7 29.4 68.6 16.9 26.5 40.2 37.6 19.2 51 4 51.6 16.2 35.9 22.4 24.569.2 22.6 20.7 30 32.6 17.3 53.2 6 33.8 9.07 25.9 10.6 14.7 39.3 14.417.6 15.5 20.1 10.6 52.5 8 19.2 5.16 14.3 6.93 9.07 28.5 8.7 9.63 9.7712.4 7.34 59.4 12 9.11 2.39 6.83 3.34 3.6 12.4 3.45 4.3 5.08 5.61 3.2858.5 24 1.88 0.465 1.21 0.543 0.609 2.62 0.561 0.814 0.953 1.07 0.73168.1

Example 52

A dasatinib monolauryl sulfate capsule dosage form was prepared byblending 9276 mg of dasatinib monolauryl sulfate prepared according tothe procedure of Example 12 which had been passed through a 325 meshsieve with 1440 mg of croscarmellose sodium and 6000 mg of anhydrouslactose in a suitable container for about 1 minute. 6324 mg ofmicrocrystalline cellulose and 720 mg of hydroxypropyl cellulose (HPC-H)which had been passed through a 40 mesh sieve were added to blend in thecontainer and further blended for 2 minutes.

240 mg of magnesium stearate which had been passed through a 40 meshsieve was added to the blend and further blended to obtain a finalblend. The final blend was filled into size 1 hard gelatin capsule.

The composition of the capsule was as follows:

Mg wt % Dasatinib monolauryl sulfate (DSB-1LS) 77.30 38.65Croscarmellose sodium 12.00 6.00 Anhydrous lactose 50.00 25.00Microcrystalline cellulose 52.70 26.35 Hydroxypropyl cellulose (HPC-H)6.00 3.00 Magnesium stearate 2.00 1.00 Total 200.00 100.00

Example 52 A

The capsules prepared in Example 52 containing dasatinib monolaurylsulfate were administered to six (6) healthy subjects under fastedconditions. This administration was a single dose, open-label,randomized, 2-treatment, 2-sequence, 2-period crossover bioavailabilitystudy in healthy subjects under fasted conditions. All subjects wererandomized to the sequences as shown in the following table with a 3-daywashout period between the periods. The Reference drug (Ref) wasSprycel®, Dasatinib monohydrate, with a strength of 50 mg (free base)while the Test drug (Test) was a capsule prepared according to theprocedure of Example 52 but containing approximately 50 mg of dasatinib(free base). The six (6) healthy subjects enrolled in this study wererandomized to one of the sequences as shown in the following table.

Sequence Period I Period II 1 Tfast Rfast

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hoursafter dosing. AUC₀₋₂₄, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults were summarized in the following table:

The Pharmacokinetic Parameters for Reference and Test Formulations 50 mgdose Treatment Parameters Mean Ref_(Fasted) C_(max) (ng/mL) 81.7 AUC₀₋₂₄(ng · h/mL) 235 AUC_(0-∞) (ng · h/mL) 238 Test_(Fasted) C_(max) (ng/mL)39.3 AUC₀₋₂₄ (ng · h/mL) 194 AUC_(0-∞) (ng · h/mL) 199 * Ref_(Fasted):Sprycel ® Tab 50 mg under fasted condition * Test_(Fasted): Test drug(Test) 50 mg under fasted condition

Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following table:

The Comparisons between Test_(Fasted) vs. Reference_(Fasted) ComparisonsParameters Geometric Mean Ratios Test~Ref C_(max) (ng/mL) 45.58%(Fasted) AUC₀₋₂₄ (ng · h/mL) 79.26% AUC_(0-∞) (ng · h/mL) 80.50%

The data shows that the compositions of the present invention exhibit adecrease of C_(max) by 0.46 fold and a decrease of AUC by 0.79 foldcompared to the U.S. FDA approved dasatinib monohydrate.

A graph of the mean plasma profiles for this Example is shown in FIG.23.

The individual subject data of 50 mg dose obtained from the study is asfollows:

Reference Drug (Sprycel ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 Mean SD CV % 0 0 0 0 0 0 0 0 0 —0.33 34.8 22.5 123 44.6 40.6 6.75 45.4 40.4 89.1 0.67 103 28 129 51.472.5 52.6 72.8 37.3 51.2 1 111 23.6 100 42.9 78.9 91.7 74.7 34.3 45.91.5 76.8 17.6 76.8 27.4 64.1 60.9 53.9 25.4 47.1 2 40.4 13.6 56.1 22.446.2 34.4 35.5 15.6 43.9 2.5 27.6 12.1 44.7 19 33.2 23 26.6 11.4 43 3 2213.5 33.9 30 27.9 18.8 24.4 7.61 31.3 4 16.2 18.1 24.1 27.1 16.9 14.619.5 4.95 25.4 6 7.46 9.11 14.7 11.3 7.7 7.57 9.64 2.88 29.9 8 4.4 5.499.08 6.93 5.2 4.01 5.85 1.88 32.1 12 1.46 2.12 4.36 2.52 2.01 2.09 2.431.01 41.5 24 0.199 0.42 0.871 0.556 0.396 0.386 0.471 0.227 48.1

Test Drug under fasted condition (Concentration (ng/mL)) Time Subject(hr) 1 2 3 4 5 6 Mean SD CV % 0 0 0 0 0 0 0 0 0 — 0.33 1.53 1.27 0 00.445 0.19 0.573 0.667 116.4 0.67 14.8 7.61 0.25 2.58 3.02 4.55 5.475.18 94.7 1 36.2 9.04 5.81 7.74 11.4 8.71 13.2 11.4 87 1.5 67 9.54 25.311.7 19.8 10.2 23.9 22 91.9 2 64.2 12.2 30.9 14.1 18 7.74 24.5 21 85.52.5 40.3 16 27.6 15.4 15.5 6.67 20.2 11.9 58.6 3 29.9 22.6 37.4 11 26.68.61 22.7 11.1 49 4 21 37.7 71.1 9.8 26.5 15.3 30.2 22.2 73.4 6 10.615.7 30.2 18.3 9.44 7.32 15.3 8.38 54.9 8 6.68 9.49 17.1 11.9 5.54 3.69.05 4.91 54.3 12 2.55 3.62 5.93 5.48 2.24 1.28 3.52 1.86 52.8 24 0.4770.593 0.924 1.07 0.527 0.653 0.707 0.237 33.5

Example 53

A dasatinib monolauryl sulfate capsule dosage form was prepared by:

-   -   (i) dissolving 6 mg of butylated hydroxytoluene (BHT) in 9756 mg        of medium chain triglycerides;    -   (ii) melting 3600 mg of Lauroyl polyoxylglycerides (Gelucire        44/14) using a water bath (60° C.);    -   (iii) adding the melted material of step (ii) to the solution of        step (i) to obtain uniform solution;    -   (iv) adding 4638 mg of dasatinib monolauryl sulfate prepared        according to the procedure of Example 48A (crystallization        Method E) which had been passed through a 60 mesh sieve to the        solution of step (iii) to obtain a uniform semi-solid        suspension. The semi-solid suspension was filled into size 1        hard gelatin capsule.

The composition of the capsule content is as follows:

mg wt % Dasatinib monolauryl sulfate 30.92 25.77 Medium chaintriglycerides 65.04 54.20 Lauroyl polyoxylglycerides (Gelucire 24.0020.00 44/14) Butylated hydroxytoluene (BHT) 0.04 0.03 Total 120.00100.00

Example 53A

The capsules prepared in Example 53 containing dasatinib monolaurylsulfate were administered to four (4) healthy subjects under fastedconditions. This administration was a single dose, open-label,randomized, 2-treatment, 2-sequence, 2-period crossover bioavailabilitystudy in healthy subjects under fasted conditions. All subjects wererandomized to the sequences as shown in the following table with a 3-daywashout period between the periods. The Reference drug (Ref) wasSprycel®, Dasatinib monohydrate, with a strength of 50 mg (free base)while the Test drug (Test) was a capsule prepared according to theprocedure of Example 53 but containing approximately 20 mg of dasatinib(free base). The four (4) healthy subjects enrolled in this study wererandomized to one of the sequences as shown in the following table.

Sequence Period I Period II 1 Tfast Rfast

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hoursafter dosing. AUC₀₋₂₄, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults were summarized in the following table:

The Pharmacokinetic Parameters for Reference and Test Formulations(Normalized to 50 mg dose) 50 mg dose Treatment Parameters MeanRef_(Fasted) C_(max) (ng/mL) 84.4 AUC₀₋₂₄ (ng · h/mL) 246 AUC_(0-∞) (ng· h/mL) 250 Test_(Fasted) C_(max) (ng/mL) 81.5 AUC₀₋₂₄ (ng · h/mL) 242AUC_(0-∞) (ng · h/mL) 246 * Ref_(Fasted): Sprycel ® Tab 50 mg underfasted condition * Test_(Fasted): Test drug (Test) 20 mg under fastedcondition

Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following table:

The Comparisons between Test_(Fasted) vs. Reference_(Fasted) (Normalizedto 50 mg dose) Comparisons Parameters Geometric Mean Ratios Test~RefC_(max) (ng/mL) 99.43% (Fasted) AUC₀₋₂₄ (ng · h/mL) 97.85% AUC_(0-∞) (ng· h/mL) 97.93%

The data shows that the compositions of the present invention exhibit adecrease of C_(max) by 0.99 fold and a decrease of AUC by 0.98 foldcompared to the U.S. FDA approved dasatinib monohydrate.

A graph of the mean plasma profiles for this Example is shown in FIG.24.

The individual subject data of 50 mg dose obtained from the study was asfollows:

Reference Drug (Sprycel ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 Mean SD CV % 0 0 0 0 0 0 0 — 0.3322.7 126 41.3 7.42 49.4 52.9 107.3 0.67 30.2 131 74.1 52 71.8 43.3 60.31 23.7 105 80.1 96.1 76.2 36.5 47.9 1.5 19.3 75.2 67.7 59.3 55.4 24.9 452 13.8 57.9 46.2 35 38.2 18.8 49.1 2.5 13 45.6 34.1 22.6 28.8 14.1 49 314.8 35.1 31.8 19.7 25.4 9.66 38.1 4 19.2 26 17.8 15.1 19.5 4.64 23.8 69.06 15.2 8.02 7.7 10 3.52 35.2 8 5.52 9.51 5.39 4.01 6.11 2.37 38.8 122.29 4.67 2.18 2.13 2.82 1.24 43.9 24 0.469 0.9 0.428 0.397 0.549 0.23643.1

Test Drug (Example 53) under fasted condition (Concentration (ng/mL)(Normalized to 50 mg dose) Time Subject (hr) 1 2 3 4 Mean SD CV % 0 0 00 0 0 0 — 0.33 0.545 8.525 2.47 0 2.875 3.9 135.4 0.67 4.975 47.5 113.250.4525 41.5 52.25 125.9 1 14.925 96.25 69.5 29.75 52.5 37 70.6 1.5 32.25117.5 42.25 50.25 60.5 38.75 63.8 2 44.5 83.75 33.75 40.25 50.5 22.5544.6 2.5 26.5 58.25 24.525 27 34 16.15 47.4 3 19.15 47.5 21.95 19.45 2713.725 50.8 4 13.55 35.75 15.3 13.575 19.55 10.825 55.4 6 15.975 18.2256.95 10.65 12.95 5.1 39.4 8 9.4 13.025 4.8 6.15 8.35 3.675 44.0 12 3.2756.175 2.1875 2.4575 3.525 1.8275 51.8 24 0.495 1.065 0.4325 0.4875 0.620.2975 48.1

Example 54

The following impurities were identified as being present in thedasatinib monolauryl sulfate prepared according to Examples 12 and 47.

Process/ Degradation Impurity Chemicals name Molecular structureimpurity Limit Impurity 1 (RRT 0.72) 2-amino-N(2-chloro-6-methylphenyl)-5- thiazolecarboxamine

Process related impurity NMT 0.20%, preferably NMT 0.15% and mostpreferably NMT 0.10% Impurity 2 (RRT 0.94) N-(2-chloro-6-methylphenyl)-2-[[6- [-1-piperanzinyl]-2- methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide

Process related impurity NMT 0.20%, preferably NMT 0.15% and mostpreferably NMT 0.10% Impurity 3 (RRT 0.96) (Dasatinib N-oxide)N-[2-Chloro-6- methylphenyl]-2-[[6- [4-(2-hydroxyethyl)-1-piperazinyl]-2- methyl-4- pyrimidinyl]amino]-5- thiazolecarboxamideN-Oxide

Degradation (oxidation degradant) NMT 0.20%, preferably NMT 0.15% andmost preferably NMT 0.10% Impurity 4 (RRT 1.10) 2-chloro-6-methylaniline

Process related impurity NMT 0.20%, preferably NMT 0.15% and mostpreferably NMT 0.10% Impurity 5 (RRT 1.28) 2-(6-chloro-2-methylpyrimidin-4- ylamino)-N-(2-chloro- 6- methylphenyl)thiazole-5-carboxamide

Process related impurity NMT 0.20%, preferably NMT 0.15 and mostpreferably preferably NMT 0.10% NMT = Not More Than

The RRT was determined using HPLC with the following parameters:

Parameter Setting/Description System HPLC Equipped with a UV/VisDetector Column YMC Pack Pro ® C18, 3 μm, 4.6 × 150 mm Detection UV at320 nm Flow rate 1.2 mL/min Injection volume 6 μL Column temperature 35°C. Sample temperature Ambient Run time 55 minutes Mode of AnalysisGradient as shown below: Time (min) Mobile phase A Mobile phase B 0 1000 2 100 0 30 63 37 38 40 60 46 0 100 48 0 100 48.5 100 0 55 100 0

The mobile phase A was 0.05 M aqueous Ammonium Acetate (pH5.25)/Acetonitrile/Methanol in a volume ratio of 90/5/5.

The mobile phase B was 0.05 M aqueous Ammonium Acetate (pH5.25)/Acetonitrile/Methanol in a volume ratio of 10/85/5.

The dosage forms prepared in Examples 49, 51-52 and the dasatinib laurylsulfate salt prepared in Examples 12-13 were tested for impurities andstability using the above HPLC method.

The test samples were prepared by respectively weighing approximately30.92 mg of dasatinib monolauryl sulfate or 41.84 mg of dasatinibdilauryl sulfate (equivalent to 20 mg of Dasatinib) into a 100 mL ambervolumetric flask, adding about 80 mL of methanol, sonicating for about 5minutes and stirring at about 800 rpms for about 5 minutes until fullydissolved. Additional methanol is added so the test sample isapproximately 0.20 mg of dasatinib per mL.

The results of the testing were as follows:

RRT 1.10 0.72 0.94 (2-Chloro-6- 1.31 (DAS-5) 0.87 (DAS PIP) 0.96methylaniline) (DAS-6) Example Initial — 0.02 0.02 0.09 0.02 0.02 12 40°C./75% R.H., 1 Month — — — 0.09 0.04 0.02 40° C./75% R.H., 3 Months —0.02 0.03 0.10 0.03 0.03 Example Initial — 0.06 0.09 0.13 — 0.02 13 40°C./75% R.H., 1 Month — 0.06 0.09 0.14 — 0.04 Example Initial — 0.03 0.030.09 0.03 0.03 49 40° C./75% R.H., 1 Month — 0.02 — 0.10 0.02 0.03 40°C./75% R.H., 3 Months — 0.04 0.02 0.09 — 0.03 Example Room temp. — 0.020.02 0.04 0.02 — 51 40° C./75% R.H., 1 Month — — — 0.02 0.03 — ExampleRoom temp. — 0.03 0.02 0.10 0.02 0.02 52 40° C./75% R.H., 1 Month — 0.040.02 0.07 0.02 0.02

The dasatinib monolauryl sulfate capsule was determined to have NMT 0.5%of any individual impurity 1, 2, 3, 4, or 5, preferably not more than0.35% of any individual impurity and most preferably not more than 0.25%of any individual impurity and the total impurity should not be morethan 1.0%, preferably not more than 0.75% and most preferably not morethan 0.60%.

The dasatinib monolauryl sulfate capsule should release not less than90%, preferably not less than 85% and most preferably not less than 80%of the dasatinib within 45 minutes of in vitro testing using a USP TypeII Apparatus (Paddle) with 500 ml of 0.1 N HCl at 75 rpm, with orwithout a sinker and 37° C.

Example 55

A dasatinib monolauryl sulfate capsule dosage form was prepared byblending dasatinib monolauryl sulfate prepared according to theprocedure of Example 48 A (crystallization Method E) with the identifiedexcipients and filled into hard gelatin capsules in the amountsindicated:

A (mg/ B (mg/ C (mg/ D (mg/ capsule) capsule) capsule) capsule)Dasatinib Monolauryl Sulfate 77.3 77.3 77.3 77.3 Medium ChainTriglyceride 251.8 209.7 209.7 (Captex ® 300) Caprylocaproyl 209.7Polyoxylglycerides (Acconon MC8-2) Butylated Hydroxytoluene 0.1 0.1 0.10.1 Lauroyl Polyoxyl-32 28.0 glycerides (Gelucire 44/14) Polysorbate 8070.0 70.0 Polyoxyl 35 Castor Oil 70.0 (Kolliphor EL) Total 357.2 357.1357.1 357.1

Example 55E

A dasatinib monolauryl sulfate capsule dosage form was prepared byadding dasatinib monolauryl sulfate prepared according to the procedureof Example 48 A (crystallization Method E) to melted polyoxyl stearateType I (Gelucire 48/16). The composition was cooled and mixed withmicrocrystalline cellulose, hydrogenated vegetable oil (LUBRITAB) andcolloidal silicon dioxide and filled in size 2 hard gelatin capsuleswith the contents of the capsule having the following composition:

mg wt % Dasatinib monolauryl sulfate, DSB-1LSC 77.30 42.94 crystallineAPI (EQ to 50 mg DSB free base) Polyoxyl stearate Type I (Gelucire48/16) 62.50 34.72 Microcrystalline cellulose 29.20 16.22 Lubritab 9.005.00 Colloidal silicon dioxide 2.00 1.11 Total 180.00 100.00

Example 55F

A dasatinib monolauryl sulfate capsule dosage form was prepared by theprocedure of Example 55, except the Lauroyl polyoxylglycerides wasreplaced with polyoxyl stearate Type I (Gelucire 48/16). The capsule hadthe following composition:

mg wt % Dasatinib monolauryl sulfate (DSB- 77.30 25.77 1LS) Medium chaintriglycerides 162.60 54.20 (Captex ® 300) Polyoxyl stearate Type I(Gelucire 60.00 20.00 48/16) Butylated hydroxytoluene (BHT) 0.10 0.03Total 300.00 100.00

Example 56

The dosage forms prepared in Examples 49, 51, 52, 53, and 55 were testedusing a USP Type II Apparatus (Paddle) with 500 ml of 0.1 N HCl at 75rpm, with a sinker and 37° C. The results of this dissolution testingare as follows:

Time (minutes) 5 10 15 30 45 60 120 (n) Ex 49 18.1 40.6 54.2 75.7 80.481.9 84.6 3 Ex 51 20.6 47.3 61.3 75.5 78.4 79.5 82.1 5 Ex 52 3.9 15.121.3 31.7 37.6 41.7 51.8 2 Ex 53 1.9 27.2 58.0 89.7 92.7 94.1 96.3 2 Ex55 A 36.2 59.0 61.9 2 Ex 55 B 91.2 94.0 95.8 2 Ex 55 C 83.7 96.3 96.4 2Ex 55 D 93.7 93.4 92.5 2 Ex 55 E 35.3 48.7 72.3 83.4 87.6 92.1 3 Ex 55 F7.2 41.5 68.9 93.8 95.4 96.1 99.5 2

Example 57

Following table describes the contents of dasatinib monolauryl sulfatecapsules prepared by dissolving the dasatinib monolauryl sulfate(according to the procedure of Example 48 A-crystallization Method E)with the indicated excipients and solvents; evaporating the solvent toform granules and blending the granules with the extra granularexcipients to form a blend which is filled into hard gelatin capsules:

A (mg/ B (mg/ C (mg/ D (mg/ E (mg/ capsule) capsule) capsule) capsule)capsule) Granules Dasatinib 77.30 77.30 77.30 77.3 77.3 monolaurylsulfate (DSB-1LS) Poloxamer 407 30.00 Poloxamer 188 25.00 Povidone K 3077.30 77.3 Hypromellose (603) 77.3 Anhydrous lactose 95.2 Polyoxylstearate 62.5 62.5 62.5 Type I (Gelucire 48/16) Solvent Alcohol Alcohol(95%)/Purified (95%)/Purified Alcohol Alcohol water (ratio water (ratioMethanol (95%) (95%) 11.1:1) 0.92:1) Extra granular Anhydrous lactose25.0 35.4 17.9 17.9 Microcrystalline 75.2 cellulose Sodium starch 10.0glycolate Colloidal silicon 5.0 dioxide Magnesium stearate 2.5Crospovidone X-10 10.0 15.0 15.0 15.0 Total 250.0 200.0 250.0 250.0 250

The dosage prepared in Example 57 were tested using a USP Type IIApparatus (Paddle) with 500 ml of 0.1 N HCl at 75 rpm, with a sinker and37° C. The results of this dissolution testing are as follows:

Time (minutes) 5 10 15 30 45 60 120 (n) Ex 57 A 30.3 48.7 59.5 66.3 68.469.8 71.3 2 Ex 57 B 0.3 13.0 32.3 52.4 58.8 61.9 65.3 3 Ex 57 C 16.241.8 58.6 74.4 82.1 85.4 89.1 2 Ex 57 D 6.2 19.3 33.9 58.8 74.5 84.093.3 2 Ex 57 E 4.0 14.67 31.17 62.35 78.03 85.74 97.76 2

Example 58

Following table describes the contents of dasatinib monolauryl sulfatecapsules prepared by wet granulation similar to the procedures describedin Examples 33, 49 and 55 dissolving the dasatinib monolauryl sulfate(according to the procedure of Example 48 A-crystallization Method E)with the indicated excipients and solvents; evaporating the solvent toform granules and blending the granules with the extra granularexcipients to form a blend which is filled into hard gelatin capsules:

A B C D E F G (mg/capsule) Granules DSB-1LS 77.30 77.30 77.30 77.3 30.9230.92 77.3 Poloxamer 407 30.0 30.0 Poloxamer 188 25.0 25.0 Caprolactam-10.0 polyvinyl acetate- polyethylene glycol graft copolymer SodiumLauryl 25.0 10.0 Sulfate Docusate sodium 11.0 Hydroxypropyl 7.5 7.5cellulose (HPC-H) Microcrystalline 67.7 81.7 21.48 21.48 72.70 celluloseMannitol 47.7 85.2 Anhydrous lactose 12.0 12.0 Sodium starch 5.0 5.0 5.01.6 1.6 5.0 glycolate Colloidal Silicon 2.5 2.5 0.8 0.8 Dioxide Lubritab62.5 Polyoxyl stearate 37.5 62.5 50.0* Type I (Gelucire 48/16)Granulating fluid Alcohol Alcohol Alcohol Alcohol Alcohol Alcohol water(95%)/water (95%)/water (95%) (95%) (95%)/water (95%)/water (ratio 1:1)(ratio 1:1) (ratio 1:1) (ratio 1:1) Extra Granular Sodium starch 5.0 5.012.5 1.6 1.6 12.5 glycolate Colloidal Silicon 2.5 2.5 5.0 0.8 0.8 5.0Dioxide Magnesium 2.5 2.5 2.5 0.8 0.8 stearate Sodium stearyl 2.5fumarate Carnauba wax 25.0 Microcrystalline 25.0 cellulose Total 250 250250 250 80 80 250 *dissolved in the granulating fluid

The dosage prepared in Example 58 were tested using a USP Type IIApparatus (Paddle) with 500 ml of 0.1 N HCl at 75 rpm, with a sinker and37° C. The results of this dissolution testing are as follows:

Time (minutes) 5 10 15 30 45 60 120 (n) Ex 58 A 5.3 16.7 25.4 40.0 46.950.4 56.2 2 Ex 58 B 18.4 35.3 43.0 53.3 59.8 63.7 71.7 2 Ex 58 C 34.0271.06 77.98 85.24 86.8 88.65 90.67 3 Ex 58 D 9.19 33.83 54.74 86.9190.10 91.13 92.54 2 Ex 58 E 1.3 5.9 11.3 27.2 37.9 43.8 57.2 2 Ex 58 F7.7 26.2 32.1 41.4 47.7 52.5 70.6 1 Ex 58 G 18.14 50.54 64.59 84.1289.59 90.64 93.00 2

Example 59A

A dasatinib monolauryl sulfate capsule dosage form was prepared bygrinding and mixing the 2319 mg of dasatinib monolauryl sulfate preparedaccording to the procedure of Example 48 A-crystallization Method E with1500 mg of polyoxyl stearate Type I (Gelucire 48/16), 375 mg ofpoloxamer 407, 1806 mg of microcrystalline cellulose and 150 mg ofsodium starch glycolate (I) in a small mixer for 15 second. Added 600 mgof purified water into the mixer and granulated for 15 second. Dried themixture in the oven at 50° C. to evaporate the water, ground into powderand passed through 40 mesh sieve. Passed 750 mg of microcrystallinecellulose, 375 mg of sodium starch glycolate (II) and 150 mg ofcolloidal silicon dioxide through 40 mesh sieve, mixed well with themixture. Passed 75 mg of sodium stearyl fumarate through 40 mesh sieveinto the container and blended with powder to obtain final blend. Thedry solid blend was filled into size 1 hard gelatin capsule.

The composition of the capsule content is as follows:

mg wt % Dasatinib monolauryl sulfate 77.30 30.92 Polyoxyl stearate TypeI 50.00 20.00 (Gelucire 48/16) Poloxamer 407 12.50 5.00 Microcrystallinecellulose 60.20 24.08 Sodium starch glycolate (I) 5.00 2.00Microcrystalline cellulose 25.00 10.00 Sodium starch glycolate (II)12.50 5.00 Colloidal silicon dioxide 5.00 2.00 Sodium stearyl fumarate2.50 1.00 Total 250.00 100.00 Purified water 20.00 N/A

Example 59B

A dasatinib monolauryl sulfate capsule dosage form with the followingcomposition was prepared by a procedure similar to that described inExample 59A:

The composition of the capsule content is as follows:

mg wt % Dasatinib monolauryl sulfate 77.30 38.65 Polyoxyl stearate TypeI 48.00 24.00 (Gelucire 48/16) Poloxamer 407 10.00 5.00 Microcrystallinecellulose 34.00 17.00 Sodium starch glycolate (I) 4.00 2.00Microcrystalline cellulose 18.70 9.35 Sodium starch glycolate (II) 5.002.50 Colloidal silicon dioxide 2.00 1.00 Sodium stearyl fumarate 1.000.50 Total 200.00 100.00 Purified water 15.00 N/A

Example 59C

A dasatinib monolauryl sulfate capsule dosage form with the followingcomposition was prepared by a procedure similar to that described inExample 59A:

The composition of the capsule content is as follows:

mg wt % Dasatinib monolauryl sulfate, 77.30 38.65 DSB-1LSC crystallineAPI (EQ to 50 mg DSB free base) Polyoxyl stearate Type I 48.00 24.00(Gelucire 48/16) Poloxamer 407 12.00 6.00 Microcrystalline cellulose34.00 17.00 Povidone K30 2.00 1.00 Microcrystalline cellulose 18.70 9.35Sodium starch glycolate 5.00 2.50 Colloidal silicon dioxide 2.00 1.00Sodium stearyl fumarate 1.00 0.50 Total 200.00 100.00 Purified water15.00 N/A

The dosage prepared in Example 59A-59C were tested using a USP Type IIApparatus (Paddle) with 500 ml of 0.1 N HCl at 75 rpm, with a sinker and37° C. The results of this dissolution testing are as follows:

Time (minutes) 5 10 15 30 45 60 120 (n) Ex 59A 31.83 66.56 76.54 81.2683.19 84.92 87.08 2 Ex 59 B 13.29 28.85 40.43 69.57 82.66 86.96 90.32 2Ex 59 C 6.87 28.81 46.59 76.05 84.99 87.16 90.11 2

Example 60

Nilotinib monolauryl sulfate capsules were prepares according to theprocedure outlined in Examples 9 and 36 with the following compositions:

A B C D E F G H I (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) Nilotinib120 120 120 120 120 120 120 120 120 MonoLauryl Sulfate Glyceryl 424 424424 424 551.2 551.2 424 551.2 551.2 Caprylate/ Caprate Polyoxyl 35 106106 212 137.8 137.8 212 137.8 137.8 Castor Oil Hard Fat 18 Butylated 0.10.2 0.2 0.2 0.1 0.1 0.2 0.2 Hydroxytoluene Capsule Type Hard Hard HardHard Hard Soft Soft Hard Hard (gelatin-based capsule capsule capsulecapsule capsule capsule capsule capsule capsule capsule) Total 650 544.1650.2 756.2 809.2 809.1 756.1 827.2 809.2

The dosage forms prepared in Examples 60A-60I were tested using a USPType II Apparatus (Paddle) with 675 ml of 0.1 N HCl at 75 rpm, with asinker and 37° C. or using a USP Type II Apparatus (Paddle) with 900 mlof 0.1 N HCl and 0.1% Tween 80 at 75 rpm, with a sinker and 37° C. Theresults of this dissolution testing are as follows:

Mean Values for Testing in 675 ml of 0.1N HCl at 75 rpm Time (min- A B CD E F G H I utes) (%) (%) (%) (%) (%) (%) (%) (%) (%) 15 3.5 17.3 19.531.5 28.6 21.4 18.4 24.9 30 12.3 27.6 36.0 47.3 42.8 36.9 30.6 35.2 6028.9 41.7 55.7 58.8 64.9 61.3 50.2 48.2 120 51.4 57.0 67.4 59.9 67.970.2 59.0 62.7 n (2) (2) (2) (2) (3) (3) (2) (3)

Mean Values for Testing in 900 ml of 0.1N HCl and 0.1% Tween 80 Time(min- A B C D E F G H I utes) (%) (%) (%) (%) (%) (%) (%) (%) (%) 1527.0 25.5 20.4 39.1 30 48.1 45.4 39.6 67.8 60 80.7 73.7 66.8 89.8 12099.4 98.7 95.5 97.5 n (3) (3) (3) (3)

Example 61A

The capsule prepared in Example 60A containing nilotinib monolaurylsulfate were administered to nine (9) healthy subjects under fasted andfed conditions. The study was a randomized, open-label, single dose,three treatment, three sequences, three periods, and crossover designwith at least a 5-day washout period between doses. The Reference drug(Ref) was TASIGNA® Capsule, nilotinib HCl, with strength of 200 mg (freebase) while the Test drug (Test) was a capsule prepared according to theprocedure of Example 60A but containing approximately 80 mg free base ofnilotinib. The nine (9) healthy subjects enrolled in this study wererandomized to one of the sequences as shown in the following table.

Period I Period II Period III Sequence 1 Ref (fasted) Test (fasted) Test(fed) Sequence 2 Test (fed) Ref (fasted) Test (fasted) Sequence 3 Test(fasted) Test (fed) Ref (fasted)

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36 and 48 hoursafter dosing. AUC₀₋₄₈, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults were normalized to 200 mg dose and are summarized in thefollowing Table:

The Pharmacokinetic Parameters for Reference and Test Formulations(Normalized to 200 mg dose) Normalized to 200 mg Treatment Parametersdose Mean Ref_(Fasted) C_(max) (ng/mL) 486 AUC₀₋₄₈ (ng · h/mL) 7108AUC_(0-∞) (ng · h/mL) 7628 Test_(Fasted) C_(max) (ng/mL) 1142 AUC₀₋₄₈(ng · h/mL) 13990 AUC_(0-∞) (ng · h/mL) 14719 Test_(Fed) C_(max) (ng/mL)1090 AUC₀₋₄₈ (ng · h/mL) 16448 AUC_(0-∞) (ng · h/mL) 17815 Ref_(Fasted):Tasigna Capsule 200 mg (free base) under fasted condition Test_(Fasted):Test drug (Test) 80 mg (free base) under fasted condition Test_(Fed):Test drug (Test) 80 mg (free base) under fed condition

Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following Table:

The Comparisons between Test vs. Reference and Test_(Fed) vs.Test_(Fasted) (Normalized to 200 mg dose) Geometric 90% ConfidenceComparisons Parameters Mean Ratios Intervals Test~Ref C_(max) 246.73%193.71%~314.26% (Fasted) (ng/mL) AUC₀₋₄₈ 196.60% 168.20%~229.80% (ng ·h/mL) AUC_(0-∞) 192.92% 165.56%~224.81% (ng · h/mL)Test_(Fed)~Test_(Fasted) C_(max) 94.70%  74.35%~120.62% (ng/mL) AUC₀₋₄₈119.05% 101.85%~139.15% (ng · h/mL) AUC_(0-∞) 122.10% 104.78%~142.28%(ng · h/mL)

The data shows that the compositions of the present invention exhibit anincrease of C_(max) by 2.5 fold and an increase of AUC by 2.0 foldcompared to the U.S. FDA approved nilotinib HCl. The data also showsthat the compositions of the present invention do not exhibit a foodeffect i.e., the compositions of the present invention exhibitcomparable pharmacokinetics under fasted and fed conditions.

The individual subject data (Normalized to 200 mg dose) obtained fromthe study is as follows:

Reference Drug (TASIGNA ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 0 0 0 0 0 0 0 0 0 0 0.533.3 54.2 54.1 41.5 105 72.0 43.5 67.6 41.4 1 132 187 276 148 467 255198 200 207 2 281 377 302 272 859 422 467 302 320 3 310 398 283 307 707475 688 333 387 4 352 378 326 314 687 508 821 341 453 5 284 294 240 244426 450 605 257 376 6 269 269 258 225 351 424 529 241 353 8 256 297 183192 292 381 456 224 295 10 230 260 183 182 289 347 527 179 273 12 198220 137 164 223 310 379 133 237 14 184 204 120 155 197 289 312 113 21624 91.7 134 59.6 77.5 118 214 246 31.8 126 36 61.3 27.5 21.9 30.2 29.366.1 133 16.5 79.6 48 51.4 BQL BQL BQL BQL 22.9 66.7 14.9 24.9

Test Drug (Example 60 A) under fasted condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 7 8 9 0 0 0 0 0 0 0 0 0 0 0.5 111 363 538188 253 605 91 0 530 1 483 958 883 863 1215 1445 580 131 888 2 978 9301030 1203 968 1543 1488 515 998 3 1073 850 998 1008 815 1470 1395 690935 4 1018 775 1080 938 733 1305 1205 725 888 5 720 710 963 753 548 1118963 583 710 6 683 573 783 708 428 985 898 453 628 8 583 503 623 570 430870 793 323 598 10 498 483 645 490 355 815 733 285 525 12 403 425 463393 298 705 618 245 415 14 340 378 420 325 273 685 585 202 348 24 95.3207 200 138 152 450 388 45.8 181 36 36.0 48.5 45.8 BQL 32.8 155 154 BQL45.5 48 BQL BQL BQL BQL BQL 78.8 65.8 BQL 46.5

Test Drug (Example 60 A) under fed condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 7 8 9 0 0 0 0 0 0 0 0 0 0 0.5 0 0 0 0 050.8 0 0 32.5 1 103 0 0 64.0 47.8 640 0 217 241 2 330 54.5 200 520 3151223 140 843 748 3 550 443 838 975 465 1460 488 903 935 4 775 758 12881073 650 1468 843 858 1555 5 953 833 1268 938 725 1395 980 708 1158 6923 768 980 850 695 1258 1008 545 1020 8 770 678 818 698 668 1178 900480 763 10 653 593 778 725 683 993 895 418 753 12 555 530 650 640 545890 730 320 645 14 503 460 548 528 485 808 648 303 545 24 163 288 315290 290 585 420 89.3 288 36 BQL 60.8 81.0 44.5 82.3 320 198 BQL 66.8 48BQL BQL BQL BQL BQL 182 109 BQL BQL

A graph of the normalized mean plasma profiles provided in Example 61Ais shown in FIG. 25.

Example 61 B

The capsules prepared in Example 60F containing nilotinib monolaurylsulfate were administered to nine (9) healthy subjects under fasted andfed conditions. This administration was a single dose, open-label,randomized, 3-treatment, 3-sequence, 3-period crossover bioavailabilitystudy in healthy subjects under fasted and fed conditions. All subjectswere randomized to the sequences as shown in the following table with awashout period of at least 5 days between the periods. The Referencedrug (Ref) was TASIGNA® Capsule, nilotinib HCl, with strength of 200 mg(free base) while the Test drug (Test) was a capsule prepared accordingto the procedure of Example 60F but containing approximately 80 mg freebase of nilotinib. The nine (9) healthy subjects enrolled in this studywere randomized to one of the sequences as shown in the following table.

Sequence Period I Period II Period III 1 Ref Tfast Tfed 2 Tfed Ref Tfast3 Tfast Tfed Ref * Ref: Reference under fasted condition; Tfast Testunder fasted condition; Tfed: Test under fed condition.

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36 and 48 hoursafter dosing. AUC₀₋₄₈, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults were summarized in the following table:

The Pharmacokinetic Parameters for Reference and Test Formulations(Normalized to 200 mg dose) Normalized to Treatment Parameters 200 mgdose (Mean) Ref_(Fasted) C_(max) (ng/mL) 580 AUC₀₋₄₈ (ng · h/mL) 8340AUC_(0-∞) (ng · h/mL) 9105 Test_(Fasted) C_(max) (ng/mL) 1302.5 AUC₀₋₄₈(ng · h/mL) 15392.5 AUC_(0-∞) (ng · h/mL) 16467.5 Test_(Fed) C_(max)(ng/mL) 1310 AUC₀₋₄₈ (ng · h/mL) 18720 AUC_(0-∞) (ng · h/mL) 20695*RefFasted: Tasigna Capsule 200 mg (free base) under fasted condition*TestFasted: Test drug (Test) 80 mg (free base) under fasted condition*TestFed: Test drug (Test) 80 mg (free base) under fed condition

Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following table:

The Comparisons between Test vs. Reference and Test_(Fed) vs.Test_(Fasted) (Normalized to 200 mg dose) Comparisons ParametersGeometric Mean Ratios T1~Ref C_(max) 247.56% (Fasted) (ng/mL) AUC₀₋₄₈193.56% (ng · h/mL) ACC_(0-∞) 192.55% (ng · h/mL)Test_(Fed)~Test_(Fasted) C_(max) 101.26% (ng/mL) AUC₀₋₄₈ 123.73% (ng ·h/mL) ACC_(0-∞) 126.12% (ng · h/mL)

The individual subject data (normalized to 200 mg dose) obtained fromthe study is as follows:

Reference Drug (TASIGNA ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 0 0 0 0 0 00 0 0 0 0 — 0.5 63.4 176 55.1 118 55.8 151 11.2 77.3 0 78.6 59.5 75.6 1202 389 171 190 413 385 86.7 255 0 232.4 142.6 61.4 2 321 570 247 2611060 762 236 495 14.4 440.7 319.0 72.4 3 339 576 288 267 964 966 428 668114 512.2 305.0 59.6 4 394 573 311 265 866 1040 500 840 202 554.6 298.153.7 5 293 447 244 192 565 769 374 613 228 413.9 199.5 48.2 6 267 417218 164 441 671 361 538 226 367.0 166.9 45.5 8 233 355 189 143 403 634289 402 226 319.3 149.7 46.9 10 171 351 161 130 340 572 305 370 212290.2 139.1 47.9 12 137 314 127 114 318 447 226 401 201 253.9 122.3 48.214 95.5 268 114 99.1 299 390 248 344 166 224.8 110.5 49.1 24 11.4 25860.1 57 268 403 24.7 136 80.8 144.3 135.1 93.6 36 BQL 118 10.8 25.3 122202 17.1 62.8 26.6 73.1 68.2 93.4 48 BQL 55.6 5.61 15.1 62.9 147 7.09 278.08 41.0 48.2 117.5

Test Drug (Example 60 F) under fasted condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 0 0 0 0 0 0 0 0 0 0 0— 0.5 0 567.5 128.75 62.25 257.5 762.5 462.5 0 14.725 250.6 282.6 112.81 275 1310 657.5 692.5 755 1430 907.5 537.5 193 750.9 417.4 55.6 2 6951407.5 1112.5 1117.5 1382.5 1955 1147.5 1102.5 475 1155.0 423.6 36.7 31217.5 1275 1072.5 905 1617.5 1780 1142.5 1505 550 1229.4 376.0 30.6 41005 1265 942.5 975 1605 1560 1155 1587.5 505 1177.8 368.0 31.2 5 667.5895 710 550 1120 1167.5 680 1130 562.5 831.4 251.4 30.2 6 567.5 952.5625 502.5 1007.5 1000 610 925 450 737.8 228.8 31.0 8 447.5 772.5 505 385790 882.5 482.5 787.5 367.5 602.2 202.2 33.6 10 347.5 762.5 452.5 350702.5 900 412.5 635 330 543.6 210.8 38.8 12 265 665 340 277.5 657.5712.5 233.5 517.5 255 435.9 200.6 46.0 14 193.25 630 272.5 213.25 600657.5 156 450 217.25 376.6 207.2 55.0 24 17.825 495 55.75 68.25 427.5540 23 221.75 106.25 217.3 213.2 98.1 36 BQL 275 15.45 BQL 208.25 224.7519.475 62.75 75.5 125.9 107.1 85.1 48 BQL 135.75 BQL BQL 118.75 145.25BQL 16.7 28.25 88.9 61.5 69.2

Test Drug (Example 60 F) under fed condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 0 0 0 0 0 0 0 0 0 0 0— 0.5 20 0 0 0 0 0 0 0 0 2.2 6.7 300.0 1 96.5 0 137.75 40.75 0 0 0 25 033.3 50.7 152.1 2 700 200 525 427.5 487.5 545 41.25 317.5 295 393.2200.4 51.0 3 1172.5 957.5 772.5 720 985 1040 625 735 562.5 841.1 205.724.5 4 1035 1275 1035 907.5 1480 2060 1387.5 1307.5 695 1242.5 395.131.8 5 875 1622.5 1105 825 1442.5 1657.5 1100 1347.5 715 1187.8 347.829.3 6 725 1440 940 722.5 1197.5 1340 962.5 1102.5 640 1007.8 284.0 28.28 615 1137.5 770 555 990 1170 762.5 897.5 575 830.3 233.3 28.1 10 5151035 660 492.5 900 1137.5 637.5 742.5 525 738.3 236.0 32.0 12 437.5 975572.5 402.5 830 922.5 582.5 635 450 645.3 214.8 33.3 14 367.5 880 465350 787.5 837.5 535 560 430 579.2 204.8 35.4 24 105 695 193 129 580 72571.5 219.5 192.75 323.4 264.3 81.7 36 BQL 497.5 23.05 24.5 352.5 347.5BQL 66.75 36 192.5 200.0 103.8 48 BQL 277.5 BQL BQL 160.75 191 BQL 19.35BQL 162.2 107.3 66.2

A graph of the mean plasma profiles provided in this Example 61B isshown in FIG. 26.

Example 61 C

The capsules prepared in Example 60G containing nilotinib monolaurylsulfate were administered to nine (9) healthy subjects under fasted andfed conditions. This administration was a single dose, open-label,randomized, 3-treatment, 3-sequence, 3-period crossover bioavailabilitystudy in healthy subjects under fasted and fed conditions. All subjectswere randomized to the sequences as shown in the following table with awashout period of at least 5 days between the periods. The Referencedrug (Ref) was TASIGNA® Capsule, nilotinib HCl, with strength of 200 mg(free base) while the Test drug (Test) was a capsule prepared accordingto the procedure of Example 60 G but containing approximately 80 mg freebase of nilotinib. The nine (9) healthy subjects enrolled in this studywere randomized to one of the sequences as shown in the following table.

Sequence Period I Period II Period III 1 Ref Tfast Tfed 2 Tfed Ref Tfast3 Tfast Tfed Ref * Ref: Reference under fasted condition; Tfast Testunder fasted condition; Tfed: Test under fed condition.

During each treatment period, blood samples were taken at 0 (prior tothe dosing), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36 and 48 hoursafter dosing. AUC₀₋₄₈, AUC_(0-∞), C_(max), T_(max), and T_(1/2) weredetermined for each subject based on non-compartmental analyses. Theresults were summarized in the following table:

The Pharmacokinetic Parameters for Reference and Test Formulations(Normalized to 200 mg dose) Normalized to Treatment Parameters 200 mgdose (Mean) Ref_(Fasted) C_(max) (ng/mL) 446 AUC₀₋₄₈ (ng · h/mL) 6831AUC_(0-∞) (ng · h/mL) 7298 Test_(Fasted) C_(max) (ng/mL) 1271 AUC₀₋₄₈(ng · h/mL) 14919 AUC_(0-∞) (ng · h/mL) 15721 Test_(Fed) C_(max) (ng/mL)1108 AUC₀₋₄₈ (ng · h/mL) 17150 AUC_(0-∞) (ng · h/mL) 17628 *RefFasted:Tasigna Capsule 200 mg (free base) under fasted condition *TestFasted:Test drug (Test) 80 mg (free base) under fasted condition *TestFed: Testdrug (Test) 80 mg (free base) under fed condition

Ln-transformed AUC_(0-t), AUC_(0-∞) and C_(max) were analyzed by ANOVA.The sequence, subject (sequence), period and treatment effects wereincluded in the model. A comparison of the data obtained from the Testand Ref dosing is shown in the following table:

The Comparisons between Test vs. Reference and Test_(Fed) vs.Test_(Fasted) (Normalized to 200 mg dose) Comparisons ParametersGeometric Mean Ratios T1~Ref C_(max) 293.64% (Fasted) (ng/mL) AUC₀₋₄₈222.56% (ng · h/mL) ACC_(0-∞) 219.50% (ng · h/mL)Test_(Fed)~Test_(Fasted) C_(max) 87.70% (ng/mL) AUC₀₋₄₈ 114.95% (ng ·h/mL) ACC_(0-∞) 112.83% (ng · h/mL)

The individual subject data (normalized to 200 mg dose) obtained fromthe study is as follows:

Reference Drug (TASIGNA ®) under fasted condition (Concentration(ng/mL)) Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 0 0 0 0 0 00 0 0 0.0 0.0 — 0.5 42.1 29.9 59.6 126 124 170 47.4 120 156 97.2 52.854.3 1 157 151 210 331 350 314 169 407 399 276.4 104.8 37.9 2 244 191365 626 487 363 285 515 381 384.1 138.7 36.1 3 344 211 556 660 493 459271 462 382 426.4 140.3 32.9 4 381 200 531 685 505 464 245 441 338 421.1149.8 35.6 5 393 163 441 566 402 404 232 316 303 357.8 119.4 33.4 6 350145 354 531 392 341 227 268 286 321.6 109.2 33.9 8 302 126 272 396 382267 207 249 276 275.2 82.5 30.0 10 235 103 228 320 320 245 181 244 260237.3 66.7 28.1 12 223 85.8 200 334 260 220 151 213 208 210.5 68.2 32.414 215 67.1 167 261 250 192 131 211 213 189.7 60.6 31.9 24 109 14.1 71.4203 172 131 77.9 156 165 122.2 59.6 48.8 36 18.9 BQL 21.8 81.7 69.4 53.623.4 43.9 89.3 50.3 27.9 55.5 48 BQL BQL BQL 37.5 32.4 18.3 9.28 BQL60.2 31.5 19.5 62.0

Test Drug (Example 60 G) under fasted condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 0 0 0 0 0 0 0 0 0 0 0— 0.5 17.65 15.6 267.5 412.5 34.75 472.5 0 14.4 405 182.2 203.8 111.8 1154.25 342.5 725 1147.5 332.5 1620 485 295 1297.5 711.0 521.3 73.3 2 725832.5 1087.5 1180 1397.5 1355 677.5 1045 1222.5 1058.1 262.9 24.8 31057.5 1242.5 1072.5 1255 1557.5 1367.5 722.5 1400 1115 1198.9 243.020.3 4 1252.5 1140 862.5 1107.5 1537.5 1262.5 655 1292.5 1057.5 1129.7256.9 22.7 5 972.5 802.5 680 840 1030 885 510 880 870 830.0 155.4 18.7 6865 645 570 792.5 950 727.5 427.5 790 787.5 728.3 158.8 21.8 8 737.5 490492.5 695 770 575 365 675 650 605.6 134.3 22.2 10 672.5 397.5 427.5 655815 532.5 297.5 585 610 554.7 159.4 28.7 12 487.5 317.5 337.5 555 682.5452.5 262.5 505 532.5 459.2 132.7 28.9 14 485 252.5 241.75 470 652.5372.5 203 482.5 492.5 405.8 148.9 36.7 24 131 70.75 64 285 497.5 225.7596.75 325 372.5 229.8 151.8 66.1 36 18.05 BQL BQL 103 207.75 49.7517.275 44.25 154 84.9 73.2 86.2 48 BQL BQL BQL 45 124.25 BQL BQL BQL82.75 84.0 39.6 47.2

Test Drug (Example 60 G) under fed condition (Concentration (ng/mL))Time Subject (hr) 1 2 3 4 5 6 7 8 9 Mean SD CV % 0 0 0 0 0 0 0 0 0 0 0 0— 0.5 0 0 0 0 0 0 0 0 0 0 0 — 1 30.5 55.5 0 59.5 0 0 262.5 20.05 71.7555.5 82.3 148.3 2 582.5 575 345 226.25 61.75 700 715 397.5 712.5 479.5234.9 49.0 3 1032.5 752.5 625 657.5 435 1150 815 735 997.5 800.0 225.428.2 4 1337.5 857.5 1005 1012.5 1247.5 1382.5 697.5 992.5 1167.5 1077.8225.6 20.9 5 870 790 837.5 1000 1352.5 1082.5 565 947.5 1207.5 961.4234.5 24.4 6 850 655 722.5 885 1165 950 455 880 1150 856.9 226.7 26.5 8660 580 552.5 797.5 970 710 392.5 827.5 945 715.0 190.1 26.6 10 742.5522.5 467.5 705 910 652.5 327.5 1005 790 680.3 215.1 31.6 12 635 475442.5 660 805 560 295 937.5 735 616.1 197.4 32.0 14 605 412.5 367.5 610690 557.5 252.5 795 657.5 549.7 172.7 31.4 24 223.25 124.25 153 402.5525 370 97.25 637.5 492.5 336.1 195.2 58.1 36 29.75 25.5 31 130.5 183140.75 32.75 250 211.25 114.9 88.1 76.7 48 BQL BQL BQL 42.5 61.25 55.75BQL 43 75.5 55.6 13.8 24.8

A graph of the mean plasma profiles provided in this Example 61C isshown in FIG. 27.

Example 62

The following impurities were identified as being present in thenilotinib lauryl sulfate salts and nilotinib lauryl sulfate dosage formsprepared in accordance with the present invention:

Impurity Chemicals name Molecular structure Impurity 1 (RRT 0.38)4-methyl-3-[[4-(pyridin-3- yl)pyrimidin-2- yl]amino]benzoic acid

Impurity 2 (RRT 0.87) methyl 4-methyl-3-[[4- (pyridin-3-yl)pyrimidin-2-yl]amino]benzoate,

Impurity 3 (RRT 1.16) N-[3-(4-ethyl-1H-imidazol-1- yl)-5-(trifluoromethyl)phenyl]-4- methyl-3-[[4-(pyridin-3- yl)pyrimidin-2-yl]amino]benzamide

The above RRT, nilotinib monolauryl sulfate salt and the dosage formsprepared in Examples 60 F and 60 G were determined or tested forimpurities and stability using HPLC with the following parameters:

Parameter Setting/Description System HPLC Equipped with a UV/VisDetector Column Water Xterra@RP18 150 × 3.0 mm 3.5 μm (for NLB-1LS)Detection UV at 250 nm Flow rate 0.8 mL/min Injection volume 10 μLColumn temperature 40° C. Sample temperature Ambient Run time 30 minutesMode of Analysis Gradient as shown below: Time (min) Mobile phase AMobile phase B 0 90 10 6 90 10 16 72 28 25 40 60 26 90 10 30 90 10

Mobile phase A was 0.25% Formic Acid/acetonitrile in a volume ratio of90/10.

Mobile phase B was 0.1% Formic Acid/acetonitrile in a volume ratio of10/90.

The test sample of the nilotinib monolauryl sulfate salt prepared inExample 46 (crystallization Method B) were prepared by weighing about7.5 mg of nilotinib monolauryl sulfate (equivalent to 5 mg of nilotinib)and transfer into a 50-mL amber volumetric flask, adding 40 mL ofdiluent (ethanol), sonicating for about 5 minutes and stirring at 800rpms for about 5 minutes until the nilotinib monolauryl sulfate isdissolved. Additional diluent is added so the test sample isapproximately 0.10 mg of nilotinib per mL.

The test sample of the dosage forms prepared in Examples 60 F and 60 Gwere prepared by the following procedure:

1. Cut the tip of the capsule with scissors and squeeze the contentsfrom the hole into the 100-mL volumetric flask. Cut the capsule into twoparts and add the parts to the flask. Add 80% full of ethanol, sonicatefor 10 minutes and stir at 800 rpm for 30 minutes to dissolve thecontents completely.

2. Dilute to volume with ethanol, mix well by inverting the flask NLT 10times

3. Pipette 3 ml into 25-mL amber volumetric flask and add ethanol tovolume, mix well by inverting the flask NLT 10 times. The test sample isapproximately 0.096 mg of nilotinib per mL.

The nilotinib dilauryl sulfate salt prepared in Example 26 were testedfor impurities and stability using HPLC with the following parameters:

Parameter Setting/Description System HPLC Equipped with a UV/VisDetector Column Inertsil ODS-3 150*4.6 mm 5 μm (for NLB-2LS) DetectionUV at 250 nm Flow rate 0.8 mL/min Injection volume 10 μL Columntemperature 40° C. Sample temperature Ambient Run time 30 minutes Modeof Analysis Gradient as shown below: Time (min) Mobile phase A Mobilephase B 0 90 10 6 90 10 16 72 28 25 40 60 26 90 10 30 90 10

The test sample of the nilotinib dilauryl sulfate salt prepared inExample 26 were prepared by weighing about 10 mg of nilotinib dilaurylsulfate (equivalent to 5 mg of nilotinib) and transfer into a 25-mLamber volumetric flask, adding 20 mL of diluent (ethanol), sonicatingfor about 5 minutes and stirring at 800 rpms for about 5 minutes untilthe nilotinib dilauryl sulfate is dissolved. Additional diluent is addedso the test sample is approximately 0.20 mg of nilotinib per mL.

The test samples tested using the above procedure and the followingresults were obtained:

RRT Condition 0.19 1.16 1.38 1.40 1.49 1.68 Example Room temp. 0.07 4660° C./75% 0.07 R.H. 2 weeks

RRT Condition 0.81 1.09 1.16 1.17 1.18 1.21 1.28 1.37 Example Room temp.0.07 0.10 0.02 26 60° C./75% 0.05 0.07 0.11 0.08 R.H. 1 week

The samples were stored in a high-density polyethylene (HDPE) bottlewith child resistant closure and foil induction seal (126 c.c, with 2˜3g of silica gel).

The above data demonstrates the nilotinib monolauryl sulfate is morestable than the dilauryl sulfate and both the monolauryl and dilaurylsulfate salts of the present invention have NMT 0.5% of any individualimpurity, preferably NMT 0.35% of any individual impurity and mostpreferably NMT 0.30% of any individual impurity and the total impurityshould be NMT 1.0%, preferably NMT 0.75% and most preferably NMT 0.60%.

RRT Condition 0.19 1.16 1.38 1.40 1.49 1.68 Example Room temp. 0.02 0.030.02 0.02 0.04 0.01 60 F 60° C./75% 0.02 0.03 0.03 0.02 0.03 0.12 R.H. 2weeks Example Room temp. 0.01 0.03 0.02 0.02 0.02 0.01 60 G 60° C./75%0.01 0.03 0.02 0.03 0.03 0.14 R.H. 2 weeks

The capsules were stored in a high-density polyethylene (HDPE) bottlewith child resistant closure and foil induction seal (126 c.c, with 2˜3g of silica gel).

Employing the above HPLC method the nilotinib lauryl sulfate dosageforms were determined to have NMT 0.5% of any individual impurity,preferably more than 0.35% of any individual impurity and mostpreferably not more than 0.25% of any individual impurity and the totalimpurity should not be more than 1.0%, preferably not more than 0.75%and most preferably not more than 0.60%.

Example 63 A

A dasatinib monolauryl sulfate tablet was prepared by grinding andmixing 7730 mg of dasatinib monolauryl sulfate prepared according to theprocedure of Example 48A, crystallization Method E with 4800 mg ofpolyoxyl stearate Type I in a small mixer for about 15 seconds. 1000 mgof purified water was added to the mixer and granulated for 15 seconds.The granules were dried in an oven at 50° C. to evaporate the water. Thedried granules were ground into a powder and passed through a 30 meshsieve. 16695 mg of microcrystalline cellulose, 1400 mg of sodium starchglycolate, 3500 mg of croscarmellose sodium and 700 mg of colloidalsilicon dioxide which had previously been passed through a 40 mesh sievewere mixed with the dried, ground and sieved granules to obtain apre-blend. 175 mg of sodium stearyl fumarate which had been previouslypassed through a 40 mesh sieve was added to the pre-blend and blended toobtain final blend. The final blend was compressed into tablets using a9.5 mm round-shaped punch and a target hardness about 5 kp.

The composition of the tablet content is as follows:

mg wt % Dasatinib monolauryl sulfate, 77.30 22.09 DSB-1LSC crystallineAPI (EQ to 50 mg free base) Polyoxyl stearate Type I 48.00 13.71Microcrystalline cellulose 166.95 47.70 Sodium starch glycolate 14.004.00 Croscarmellose sodium 35.00 10.00 Colloidal silicon dioxide 7.002.00 Sodium stearyl fumarate 1.75 0.50 Total 350.00 100.00 Purifiedwater 10.00 N/A

Example 63 B

A dasatinib monolauryl sulfate tablet was prepared by grinding andmixing 2319 mg of dasatinib monolauryl sulfate prepared according to theprocedure of Example 48A, crystallization Method E with 1800 mg ofpolyoxyl stearate Type I and 1800 mg of microcrystalline cellulose (PartI) in a small mixer for about 15 seconds. 450 mg of purified water wasadded to the mixer and granulated for 15 seconds. The granules weredried in an oven at 50° C. to evaporate the water. The dried granuleswere ground into a powder and passed through a 40 mesh sieve. 2638.5 mgof microcrystalline cellulose (Part II), 420 mg of sodium starchglycolate, 1260 mg of croscarmellose sodium and 210 mg of colloidalsilicon dioxide which had previously been passed through a 40 mesh sievewere mixed with the dried, ground and sieved granules to obtain apre-blend. 52.5 mg of sodium stearyl fumarate which had been previouslypassed through a 40 mesh sieve was added to the pre-blend and blended toobtain final blend. The final blend was compressed into tablets using a9.5 mm round-shaped punch and a target hardness about 5 kp.

The composition of the tablet content is as follows:

mg wt % Dasatinib monolauryl sulfate, 77.30 22.09 DSB-1LSC crystallineAPI (EQ to 50 mg DSB free base) Polyoxyl stearate Type I 60.00 17.14Microcrystalline cellulose (I) 60.00 17.14 Microcrystalline cellulose(II) 87.95 25.13 Sodium starch glycolate 14.00 4.00 Croscarmellosesodium 42.00 12.00 Colloidal silicon dioxide 7.00 2.00 Sodium stearylfumarate 1.75 0.50 Total 350.00 100.00 Purified water 15.00 N/A

Example 63 C

The dasatinib monolauryl sulfate tablets prepared in Examples 63 A and63 B were tested using a USP Type II Apparatus (Paddle) with 500 ml of0.1 N HCl at 75 rpm, with a sinker and 37° C. The results of thisdissolution testing are as follows:

Time 63 A 63 B (minutes) (%) (%) 5 65.3 66.8 10 79.4 81.1 15 83.5 84.330 86.1 87.2 45 86.8 88.7 60 87.4 89.7 120 88.0 91.1 n 2 3

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein, any of the terms “comprising,” “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding any equivalents ofthe features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe invention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theconcepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

We claim:
 1. A method for treating chronic myeloid leukemia comprisingorally administering to a patient in need of such therapy a capsulecomprising: about 5 wt % to about 50 wt % of nilotinib lauryl sulfatesalt; and about 5 wt % to about 90 wt % of one or more excipients with ahydrophilic-lipophilic balance (HLB) value of less than 10 selected froma group consisting of a wetting agent, an emulsifying agent, asolubilizing agent, a surfactant or a combination thereof; wherein thecapsule exhibits: a dissolution rate of about 10% to about 85% after 30minutes of testing and about 40% to about 95% after 60 minutes oftesting using a USP Type II Apparatus (Paddle) with a 0.1 N HCl and 0.1%Tween 80 media at 75 rpm, with or without a sinker at 37° C.; andproduces an AUC₀₋₄₈ of about 69.95 ng·hr/mL/mg to about 133.83ng·hr/mL/mg when administered as a single dose of the capsule to one ormore human patients or healthy human subjects under a fasted state; aC_(max fed)/C_(max fast) ratio of about 0.80 to about 1.25 wherein theC_(max fed) is a maximum nilotinib plasma concentration obtained byadministering a single dose of the capsule to one or more human patientsor healthy human subjects under a fed state and the C_(max fast) is amaximum nilotinib plasma concentration obtained by administering asingle dose of the capsule to the one or more patients or subjects undera fasted state; an AUC_(0-∞ fed)/AUC_(0-∞ fast) ratio of about 0.80 toabout 1.25 wherein the AUC_(0-∞ fed) is an AUC obtained from the time ofadministration of a single dose of the capsule to one or more humanpatients or healthy human subjects under a fed state to infinity and theAUC_(0-∞ fast) is an AUC obtained from the time of administration of asingle dose of the capsule to the one or more patients or subjects undera fasted state to infinity; and when administered as a single dose toone or more human patients or healthy human subjects under a fastedstate at least a 25% greater AUC₀₋₄₈ compared to a similar dose ofnilotinib free base administered by a capsule comprising nilotinibmonohydrate monohydrochloride, colloidal silicon dioxide, crospovidone,lactose monohydrate, magnesium stearate and poloxamer
 188. 2. The methodof claim 1 wherein the one or more excipients with an HLB value of lessthan 10 comprises a medium chain monoglyceride, a medium chaindiglyceride, a medium chain triglyceride, a vegetable oil, ahydrogenated vegetable oil, a fatty acid ester, a fatty acid alcohol, apolyoxylglyceride, a sorbitan ester, a sorbitan fatty acid ester, aphospholipid or a combination thereof.
 3. The method of claim 1 whereinthe one or more excipients with an HLB value of less than 10 comprises amedium chain monoglyceride, a medium chain diglyceride, a medium chaintriglyceride, or a combination thereof.
 4. The method of claim 1 whereinthe one or more excipients with an HLB value of less than 10 comprise aglyceryl caprylate/caprate, a glyceryl caprylate, a glyceryl caprate, aglyceryl monocaprylocaprate or a mixture thereof.
 5. The method of claim1 wherein the capsule further comprises about 1 wt % to about 60 wt % ofone or more excipients with an HLB value of 10 or greater selected fromthe group consisting of a wetting agent, an emulsifying agent, asolubilizing agent, a surfactant or a combination thereof.
 6. The methodof claim 5 wherein the one or more excipients with an HLB value of 10 orgreater comprise a polyoxylethylene stearate, a fatty acid alcohol, afatty alcohol acid or amide ethoxylate, a monoglyceride ethoxylate, asorbitan ester ethoxylate, an alkyl polyglycoside, a polyoxyethylenecastor oil, a polyoxyethylene hydrogenated castor oil, a poloxamer, atyloxapol, a fatty acid ester or fatty acid alcohol of a polyglycerideand a combination thereof.
 7. The method of claim 6 wherein the one ormore excipients with an HLB value of 10 or greater comprises apolyoxylethylene stearate or a polyoxyethylene castor oil.
 8. The methodof claim 1 wherein the C_(max fed)/C_(max fast) ratio is a geometricmean ratio and the AUC_(0-∞ fed)/AUC_(0-∞ fast) ratio is a geometricmean ratio.
 9. The method of claim 1 wherein the nilotinib laurylsulfate capsule is not administered with a dosage form that decreasesthe pH of the patient's stomach.
 10. The method of claim 1 wherein thenilotinib lauryl sulfate capsule is not administered with an amount ofan acidifying agent to decrease the pH of the patient's stomach.